2-thio-substituted imidazole derivatives and their use in pharmaceutics

ABSTRACT

The invention relates to 2-thio-substituted imidazole derivatives of the formula I 
                         
in which the radicals R 1 , R 2 , R 3  and m are as defined in the description. The compounds according to the invention have immunomodulating and/or cytokine-release-inhibiting action and are therefore suitable for treating disorders associated with a disturbed immune system.

The present invention relates to 2-thio-substituted imidazolederivatives having immunomodulating and cytokine-release-inhibitingaction, to pharmaceutical compositions comprising these compounds and totheir use in pharmacy.

Pharmacologically active imidazole compounds with anti-inflammatoryactivity are already known. Thus, inter alia, compounds having4,5-di(hetero)arylimidazole moieties have been examined more closely,and various pharmaceutical actions thereof have been described. Alsoknown are compounds which are substituted in the 2-position. U.S. Pat.No. 4,585,771 discloses 4,5-diphenylimidazole derivatives which aresubstituted in the 2-position by a pyrrolyl, indolyl, imidazolyl orthiazolyl radical and which have anti-inflammatory and antiallergicactivity. U.S. Pat. Nos. 4,528,298 and 4,402,960 describe4,5-di(hetero)arylimidazole derivatives which are substituted in the2-position via a thio, sulfinyl or sulfonyl group by a phenyl, pyridyl,N-oxypyridyl, pyrimidyl, thiazolyl or thienyl radical and which haveanti-inflammatory and antiallergic activity. U.S. Pat. Nos. 4,461,770,4,528,298 and 4,584,310 (EP 004 648 A) describe4-(5-aryl)-5-(4-heteroaryl)imidazole derivatives which are substitutedin the 2-position via a thio, sulfinyl or sulfonyl group by asubstituted or unsubstituted aliphatic hydrocarbon and which, interalia, have anti-inflammatory action. Imidazole compounds havingimmunomodulating and cytokine-release-inhibiting action are described inWO 02/066458, WO 02/076951 and DE 102 22 103. Further imidazolecompounds having anti-inflammatory action are described in WO 96/03387,EP 005 545 (U.S. Pat. Nos. 4,440,776; 4,355,039; 4,269,847), EP 236 628(U.S. Pat. No. 4,686,231), DE 35 04 678, U.S. Pat. Nos. 4,190,666,4,402,960 and 4,585,771. EP 372 445 (U.S. Pat. Nos. 5,318,984;5,166,214) and U.S. Pat. No. 5,364,875 describe imidazole compoundshaving antihypercholesterolemic activity.

WO 00/17192 (DE 198 42 833) relates to 4-heteroaryl-5-phenylimidazolederivatives which are substituted in the 2-position by a phenylalkylthiogroup. These compounds act as anti-inflammatories and inhibitors ofcytokine release. WO 99/03837 and WO 93/14081 describe 2-substitutedimidazoles which inhibit the synthesis of a number of inflammatorycytokines. The compounds described in WO 93/14081 have in the2-position, attached via a sulfur atom, a phosphorus-containingsubstituent or an aryl or heteroaryl substituent. WO 91/10662 and WO91/13876 describe imidazole derivatives which inhibit the acyl-coenzymeA:cholesterol-O-acyl transferase and binding of thromboxane TxA₂. WO95/00501 describes imidazole derivatives which can be used ascyclooxygenase inhibitors.

J. Med. Chem. 1996, 39, 3927-37 describes compounds having5-lipoxygenase- and cyclooxygenase-inhibiting action,2-(4-methylsulfinylphenyl)-4-(4-fluorophenyl-5-(pyrid-4-yl)imidazolealso having cytokine-inhibiting action.

Further 2-thio-substituted imidazole derivatives are described in JP01-040 467, SU 1 415 725, Acta Chim. 1969, 61, 69-77, J. prakt. Chem.1972, 314, 785-792 and DE 101 14 775, Indian J. Chem., Sect. B, 1983,22B(3), 268-269, Bioorganic & Medicinal Chem. Lett., Vol 5, No. 2,177-180, 1995, Phosphorus Sulfur 1988, 35(1-2), 83-88, Arch. Biochem.Biophys. Vol. 297, 258-264, 1992, J. Med. Chem. 1995, 38, 1067-1083,Helv. Chim. Acta 82, 1999, 290-296, Helv. Chim. Acta 81, 1998,1585-1595.

In spite of the fact that numerous compounds are known, there istherefore still a need for compounds having anti-inflammatory actionwhich inhibit cytokine release.

It is an object of the invention to provide such compounds.

Surprisingly, it has now been found that certain 2-substituted imidazolederivatives have high immunomodulating and/or cytokine-releaseinhibiting activity.

Accordingly, the present invention provides 2-thio-substituted imidazolederivatives of the formula I

in which

-   -   R¹ is C₁-C₆-alkyl, C₃-C₇-cycloalkyl or aryl which is        unsubstituted or substituted by a halogen atom, by C₁-C₆-alkyl        or by halo-C₁-C₆-alkyl;    -   R² is selected from the group consisting of        -   a) aryl-C₁-C₄-alkyl, where the aryl radical may have one,            two or three substituents independently of one another            selected from the group consisting of C₁-C₆-alkyl,            C₁-C₆-alkoxy, halogen, C₁-C₆-alkylsulfanyl,            C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl and hydroxyl, and        -   b) C₁-C₆-alkyl which is unsubstituted or substituted by CN            or halogen;

-   -   R³ is selected from the group consisting of        -   a) NR⁴R¹⁰;        -   b) NR⁷COR¹⁰;        -   c) NR⁷COOR¹⁰;        -   d) NR⁷CONR⁷R¹⁰;        -   e) NR⁷CONR⁷COR¹⁰;        -   f) OR¹⁰;        -   g) S(O)_(m)R¹⁰;        -   h) halogen;        -   i) OH;        -   j) N₃        -   k) NH₂        -   l) SH;    -   where R³ is not OH, halogen, C₁-C₆-alkylthio or C₁-C₆-alkoxy if        R² is phenyl-C₁-C₄-alkyl and the phenyl radical has a        C₁-C₆-alkylsulfanyl, C₁-C₆-alkylsulfinyl or C₁-C₆-alkylsulfonyl        substituent;    -   R⁴ is H or a physiologically cleavable group,    -   R⁵ and R⁶, which may be identical or different, are H, halogen,        OH, C₁-C₆-alkoxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,        C₁-C₆-alkylsulfanyl, NH₂, C₁-C₆-alkylamino or        di-C₁-C₆-alkylamino;    -   R⁷ is R⁴, C₁-C₆-alkyl or benzyl;    -   R¹⁰ has one of the meanings below:

-   -   f) C₁-C₆-alkyl which is substituted by 2 or 3 phenyl groups;    -   g) trifluoromethyl (in particular, if R³ is one of the        radicals b) to f))    -   A is straight-chain or branched C₁-C₆-alkylene, C₂-C₆-alkenylene        or C₃-alkynylene;    -   B is selected from the group consisting of

-   -   -   f) OC₁-C₆-alkyl;        -   g) NR¹¹R¹²;        -   h) OH;        -   i) halogen;        -   j) C₁-C₆-alkylsulfanyl

    -   R¹¹ and R¹², which may be identical or different, are H,        C₁-C₆-alkyl or phenyl;

    -   Hy is a 3- to 10-membered non-aromatic mono-, bi- or tricyclic        carbocycle which may or may not be fused with a benzene ring;

    -   Ar is a 5- or 6-membered aromatic heterocycle which has 1, 2 or        3 heteroatoms independently of one another selected from the        group consisting of O, S and N and which may or may not be fused        with a benzene ring;

    -   Het is a 5- or 6-membered non-aromatic heterocycle which has 1,        2 or 3 heteroatoms independently of one another selected from        the group consisting of O, S and N, which may or may not be        fused with a benzene ring and which may or may not be bridged        bicyclically or tricyclically;

    -   m is 0, 1 or 2;

    -   n is 1, 2, 3, 4 or 5;        and the tautomers, optic isomers and physiologically acceptable        salts thereof.

If the compounds according to the invention have centers of asymmetry,the scope of the invention includes both racemates and optical isomers(enantiomers, diastereomers). In the compounds according to theinvention, the following tautomeric equilibrium may be present:

The invention embraces both tautomeric forms.

The invention also embraces the physiologically acceptable salts of thecompounds of the formula I. In the present case, these are in particularacid addition salts. For acid addition salts, what is used are inorganicacids, such as hydrochloric acid, sulfuric acid or phosphoric acid, ororganic acids, such as tartaric acid, citric acid, maleic acid, fumaricacid, malic acid, mandelic acid, ascorbic acid, gluconic acid and thelike.

The term “alkyl” (also in combination with other groups, such asphenylalkyl, alkylsulfonyl, alkoxy, etc.) embraces straight-chain andbranched alkyl groups having 1 to 6 or 1 to 4 carbon atoms, such asmethyl, ethyl, n- and isopropyl, n-, iso- and t-butyl, sec-butyl,n-pentyl, isoamyl, neopentyl and n-hexyl. This applies correspondinglyto “C₁-C₆-alkylene”.

The term “carbocycle” embraces saturated or unsaturated non-aromaticmonocyclic, bicyclic and tricyclic hydrocarbons. The hydrocarbons can befused with one or two benzene rings. Monocyclic hydrocarbons areC₃-C₆-cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl. Examplesof bi- and tricyclic hydrocarbons and benzo-fused carbocycles areindanyl, decalinyl, tetralinyl, fluorenyl, dihydroanthracenyl,dibenzosuberenyl, norbornyl or adamantyl. Examples of substitutedcarbocycles are methylcyclopropyl or methylcyclohexyl. Preference isgiven to unsubstituted radicals.

The term “aryl” embraces aromatic ring systems, such as phenyl ornaphthyl.

The term “halogen” represents a fluorine, chlorine, bromine or iodineatom, in particular a fluorine or chlorine atom.

The term “halo-C₁-C₆-alkyl” embraces mono- or polyhalogenatedstraight-chain and branched alkyl groups having 1 to 6 and in particular1 to 4 carbon atoms. Preferably, 1, 2, 3, 4 or 5 halogen atoms arepresent. Preferred halogen atoms are F and Cl. Examples ofhalo-C₁-C₆-alkyl are —CH₂Cl, —CH₂CH₂Cl, —CH₂CCl₃, —CF₃, —CHF₂, —CH₂F,—CH₂CF₃ and —CF₂CF₃. CF₃ is preferred.

A physiologically cleavable group is a group which can be cleaved fromthe remainder of the molecule under physiological conditions,enzymatically or chemically. Examples are —COR¹⁴, —CO₂R¹⁴, —CONH₂,—CONHR¹⁴, —CHR¹⁶—OR¹⁴, —CHR¹⁶—O—COR¹⁴, —COC(R¹⁶)₂—OH, —COR¹⁵, SO₂R¹⁵ and—SO₂R¹⁴, where R¹⁴ is C₁-C₆-alkyl or CF₃, R¹⁵ is phenyl or tolyl (inparticular p-tolyl) and R¹⁶ is H or C₁-C₆-alkyl.

The aromatic 5- or 6-membered heterocycle is in particular unsubstituted(R⁵, R⁶=H) or substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- or3-thienyl, 2- or 3-furyl, thiazolyl, imidazolyl, oxazolyl, isothiazolyl,pyrazolyl, isoxazolyl, triazolyl or pyrimidyl. Preferred substituentsare one or two groups independently of one another selected from thegroup consisting of halogen, in particular Cl, and C₁-C₆-alkyl. Thesubstituent(s) are attached to a carbon atom or a nitrogen atom of thearomatic radical. Preferred are unsubstituted radicals. Examples ofsubstituted radicals are chlorothienyl, in particular5-chlorothien-2-yl, chlorofuryl, in particular 5-chlorofur-2-yl,examples of fused radicals are benzofuranyl, benzothiazolyl andbenzothiophene.

The non-aromatic 5- or 6-membered heterocycle may be saturated orunsaturated. It is preferably unsubstituted or substitutedtetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,N-methylpyrrolidinyl, N-ethylpyrrolidinyl, piperazinyl or morpholinyl,where the heterocycle may be attached via a nitrogen heteroatom or aring carbon atom or may be substituted. Preferred substituents are oneor two radicals independently of one another selected from the groupconsisting of halogen, in particular Cl, and C₁-C₆-alkyl. Preference isgiven to unsubstituted radicals.

is substituted or unsubstituted cyclopropyl, cyclobutyl, cycloheptyland, in particular, cyclopentyl and cyclohexyl. R⁵ and R⁶ are preferablyindependently of one another H, halogen or C₁-C₆-alkyl. Examples ofsubstituted cycloalkyl groups are methylcyclopropyl or methylcyclohexyl.Preference is given to unsubstituted radicals.

Phenyl-C₁-C₄-alkyl is in particular benzyl, 1-phenylethyl or2-phenylethyl.

R¹ is preferably a phenyl radical and in particular a halogen-, CF₃- orC₁-C₆-alkyl-substituted phenyl radical, a fluorine-substituted phenylradical being particularly preferred. The substituent is preferably inthe 3- and in particular in the 4-position. Examples of substitutedphenyl radicals are 4-fluorophenyl, 2,4-difluorophenyl,3-trifluoromethyl, 3-tolyl or 3-chlorophenyl.

R² is preferably a benzyl, C₃-C₆-cycloalkyl, C₄-C₇-methylcycloalkyl orC₁-C₆-alkyl radical, where the phenyl group of the benzyl radical may besubstituted as indicated above. Preferred substituents of the phenylgroup of the benzyl radical are C₁-C₆-alkylsulfanyl, C₁-C₆-alkylsulfinyland C₁-C₆-alkylsulfonyl. Examples of R² are CH₃, CH₃CH₂, (CH₃)₂CH,CH₂CN, CH₂CF₃, CF₃ and cyclopropyl.

R³ is preferably the radical of the formula

in which R⁴, R⁵ and R⁶ and also A are as defined above. R⁵ and R⁶ arepreferably H, methyl, methoxy or chlorine. If the phenyl ring of thisgroup is substituted, the radicals R⁵ and R⁶ are preferably located inthe 3- and/or 4-position.

Furthermore, R³ is preferably

-   -   a) NR⁴R¹⁰, where R¹⁰ is cyclopropyl, cyclopropylmethyl,        cyclopentyl, cyclohexyl or cycloheptyl;    -   b) NR⁴R¹⁰, where R¹⁰ is C₁-C₆-alkyl, in particular methyl, ethyl        or isopropyl, or is 3,3-diphenylpropyl or 1,3-diphenylprop-2-yl;    -   c) NR⁴R¹⁰, where R¹⁰ is A-B and B is OH, C₁-C₆-alkyoxy, NR¹¹R¹²        or phenyl;    -   d) NR⁷COR¹⁰, where R¹⁰ is A-B and B is phenyl;    -   e) NR⁷COOR¹⁰, where R¹⁰ is C₁-C₆-alkyl.

A is preferably C₁-C₂-alkylene and in particular ethylidene.

m is preferably 0.

A particularly preferred embodiment are the compounds of the formula Iin which R¹ is 4-fluorophenyl, R² is C₁-C₆-alkyl or benzyl, where thephenyl group of the benzyl radical may be substituted as indicatedabove; R³ is the radical of the formula

where R⁴, R⁵, R⁶ and A are as defined above, and m is 0.

A further preferred embodiment are compounds of the formula I in whichR² is C₁-C₆-alkyl, in particular methyl, and R¹ is halophenyl orhalo-C₁-C₆-alkylphenyl, in particular 4-fluorophenyl,2,4-difluorophenyl, 4-trifluoromethylphenyl or 3-trifluoromethylphenyl.R³ is then preferably as defined below:

-   a) halogen, in particular F or Cl;-   b) OH or O C₁-C₆-alkyl, in particular methoxy and isopropoxy,-   c) phenylamino;-   phenyl- or naphthyl-C₁-C₄-alkylamino wherein the phenyl group may be    substituted by 1 or 2 halogen, in particular F or Cl, C₁-C₆-alkoxy    or C₁-C₆-alkyl. The amino group may additionally be substituted by    C₁-C₆-alkyl. Examples of such radicals are benzylamino,    4-methoxybenzylamino, 4-methylbenzylamino, 4-chlorobenzylamino,    3,4-dichlorobenzylamino, 2-phenylethylamino, 1-phenylethylamino,    1-naphth-1-yl-amino 1-naphth-2-ylamino; 1-phenylprop-3-ylamino,    3-phenylpropylamino, 1-(4-isobutylphenyl)ethylamino;

-    in which A is C₁-C₂-alkylene, R⁵ and R⁶ are H and

-    is thienyl, furyl, 2-, 3- or 4-pyridyl, thiazolyl, oxazolyl,    benzothiophenyl or benzofuranyl, where the heterocyclic radicals may    be substituted by halogen, in particular F or Cl, or C₁-C₆-alkyl.

-    in which A, R⁵, R⁶ and

-    are as defined under e).-   g) NH—C₁-C₆-Alkyl which is substituted by 2 or 3 phenyl groups, for    example 3,3-diphenylpropylamino, 1,3-diphenylprop-2-ylamino;

-    in which A is C₁-C₂-alkylene, R⁵ and R⁶ are H and

-    is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidine, N-methyl- or    N-ethylpyrrolidine;

-    in which R⁵, R⁶ and

-    are as defined under h);-   j) —NH—COOR¹⁰, in which R¹⁰ is C₃-C₆-cycloalkyl;-   k) —NH—CO—NHR¹⁰, in which R¹⁰ is C₃-C₆-cycloalkyl;-   l) —NH—COR¹⁰, in which R¹⁰ is C₃-C₆-cycloalkyl-C₁-C₄-alkyl, for    example cyclopentylmethyl, cyclohexylmethyl;-   m) NH—CONH CO phenyl;-   n) -A-C₃-C₆-cycloalkyl, in which A is C₁-C₂-alkylene, for example    cyclopentylmethylamino, cyclohexylmethylamino.

The compounds according to the invention can be prepared in acorresponding manner according to the processes described in the stateof the art mentioned at the outset, in particular WO 00/17192. Thepreparation according to the following two-step process has been foundto be particularly expedient. In the first step, a substitutedimidazole-2-thione of the formula II is initially prepared. In thesecond step, this is then reacted such that the 2-thio-substitutedimidazole derivatives of the formula I are obtained with introduction ofthe desired substituent R².

1) Preparation of the imidazole-2-thione

Imidazole-2-thiones where R³=H, halogen (Br, Cl, F), O-alkyl or S-alkylare prepared according to process A or B. By way of example, process Ais illustrated for compounds in which R¹ is 4-fluorophenyl and R³ is H,process B is illustrated for compounds in which R¹ is 4-fluorophenyl andR³ is Cl, (25a), F (25b) or O-alkyl (25c, 25d) (the numbers in bracketsrefer to the numbers of the examples). 2-Thio-substituted imidazolederivatives where R³=NR⁴R¹⁰ are not prepared from the correspondingimidazole-2-thiones where R³=NR⁴R¹⁰ but in a different manner accordingto process C. 2-Thio-substituted imidazole derivatives where R³=O-alkylor S-alkyl can be prepared both according to process C and according toprocess B.

Process A

The synthesis of the substituted imidazole-2-thiones where R³=H iscarried out according to the course of the reaction of scheme 1, usingethyl isonicotinate and 4-fluorophenylacetonitrile as startingmaterials.

The starting materials are converted in a condensation reaction with theaid of metallic sodium in an alcohol, for example ethanol, into2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (IIIa). The cyano groupis then removed by hydrolysis, for example with hydrobromic acid, anddecarboxylation, giving 2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (IVa).In the next step, IVa is converted by treatment with ammoniumchloride/sodium acetate in an alcoholic solvent, such as methanol, intothe oxime (Va). By reaction with p-toluenesulfonyl chloride in pyridine,the latter is converted into the tosylate (VIa). From the tosylate, thethione compound (IIa) is obtained by treatment with sodium ethoxide andreaction of the azirene intermediate formed with potassium thiocyanate.

Process B:

The preparation of the compounds according to the invention in which thepyridine radical has a halogen, O-alkyl or S-alkyl substituent iscarried out according to scheme 2 via corresponding2-halopyridyl-substituted imidazolthiones (process B). The preparationof these imidazolthiones is illustrated using the 2-fluoro-substitutedpyridinine compound (R³=2-F) where R¹=p-fluorophenyl as an example.Imidazolthiones carrying, in position 4, alkyl and cycloalkyl radicals(R¹=C₁-C₄-alkyl, C₃-C₇-cycloalkyl) are obtained in an analogous mannerstarting with the appropriately substituted 2-fluoro-γ-picoline ketones.

γ-Picoline (R³=H) and the halogen-(R³=F, Cl, Br, I), methoxy-(R³=OCH₃)and methylthio-(24, R³=SCH₃) substituted γ-picolines are lithiated inthe γ-methyl group with exclusion of moisture, in solvents suitable forthis purpose, such as hydrocarbons, ethers and mixtures thereof (forexample hexane, tetrahydrofuran, ethylene glycol, dimethyl ether), usinglithium diisopropylamide (LDA) and then condensed with suitablecarboxylic acid derivatives (R¹—COOR, R¹—CONR₂, R¹—CN). Here, the amidesof the N,O-dimethylhydroxylamine (R¹—CONCH₃(OCH₃), 20) have been foundto be particularly suitable. Using nitrites and bases, for example amylnitrite /sodium methoxide, or using alkali metal nitrite and acid, theγ-picolyl ketones (IVb) formed are nitrosated in the γ-picolyl position.The reaction of the γ-picolyl ketone, dissolved in glacial acetic acid,with aqueous sodium nitrite solution has been found to be particularlyadvantageous. During this reaction, the nitrosoketones are convertedcompletely into the tautomeric oxime ketones (VIIb).

The oxime ketones are reduced in alcoholic solution in the presence ofhydrogen and mineral acids, for example HCl, using palladium-on-carbon,to give the ammonium salts of the amine ketones (VIIIb) (23b).

Alternatively, other oxime ketones can be reduced in alcoholic solutionin the presence of mineral acids, for example H₂SO₄, using zinc dust, togive the corresponding ammonium ketones (23f).

These ammonium ketone compounds afford, after action of alkali metalthiocyanates, for example potassium thiocyanate in dry dimethylformamide(DMF) with heating under reflux, the imidazolethiones of the formula IIbwhere R³=F, Cl, Br, O-alkyl or S-alkyl, as yellow solids (24b).

The preparation of the compounds according to the invention in which thepyridine radical has an ether (R³=OR¹⁰), thioether (R³=SR¹⁰) or aminosubstituent (R³=NR⁴R¹⁰) is carried out according to scheme 4 or scheme5, via corresponding 2-halopyridyl-substituted imidazolethiones (processC, see below).

2) Preparation of the 2-thioimidazole compound

The imidazolethione compounds of the formula II obtained according toprocess A or B are, by substitution of the sulfur atom in the2-position, converted into the compounds of the formula I according tothe invention. The substitutions, as shown in an exemplary manner forsome compounds in scheme 3, are carried out in a known manner using anucleophilic substitution reaction. Here, the compound IIa or IIb isreacted with R²—X in an inert polar solvent, such as an alcohol. X is aneasily exchangeable group, such as Hal, in particular Cl, Br, I,methylsulfonyl, tosyl, etc. Suitable processes are known to the personskilled in the art and described, for example, in WO 00/17192, EP 0 372445 and U.S. Pat. No. 4,440,776. The compounds R²—X are known or can beprepared by known processes as described, for example, in WO 00/17192.

Process C:

Compounds according to the invention in which R³ is an amino substituent(R³=NR⁴R¹⁰) are prepared from 2-thioimidazoles using4(5)-(2-halopyridin-4-yl) substitution. The process (process C) isillustrated in scheme 4 using the 2-benzylamino (R³=NH—CH₂Ph) whereR¹=p-fluorophenyl as an example (25f).

The starting materials (Ib) can be prepared by the process describedabove.

The reaction is expediently carried out in the amine in question, whichis preferably employed in an amount of from 5 to 20 mole equivalents permole equivalent of the compound (Ib). The reaction temperature isgenerally in the range from 100 to 200° C. If desired, it is alsopossible to use an inert solvent, such as dioxane, dimethylformamide,diethylacetamide, tetraethylurea, methylpyrrolidone, etc., andappropriate additives, such as alkali metal carbonates or monovalentcopper halides (to neutralize acid equivalents released or to catalyzethe elimination of halogen).

The compounds according to the invention in which R³ is an alkoxysubstituent or alkylthio substituent (R³=O—C₁-C₆-alkyl, S—C₁-C₆-alkyl)can not only be prepared by process B (starting with appropriatelysubstituted picolines) but also by process C, starting with the4(5)-(2-halopyridin-4-yl)-substituted 2-thioimidazoles.

Process D:

The compounds according to the invention in which R³ is an alkoxysubstituent (R³=O—C₁-C₆-alkyl) can not only be prepared by process B orC, but also by process D, starting with the4(5)-(2-halopyridin-4-yl)-substituted 2-thioimidazoles. The process isillustrated in scheme 5, using the 2-isopropyloxypyridinine compounds(R³=OCH(CH₃)₂) where R¹=p-fluorophenyl as an example.

The starting materials (Ib) can be prepared by the processes describedabove.

The reaction is expediently carried out in the alcohol, which ispreferably used in an amount of from 5 to 20 mole equivalents per moleequivalent of the compound (Ib), in the case of lower alcohols also upto one hundred mole equivalents, in the presence of a strong acid, suchas HCl or trifluoroacetic acid, methanesulfonic acid, etc. The reactiontemperature is generally within the boiling range of the lower alcohols,in the case of higher alcohols in the range from 100 to 200° C. It hasbeen found to be favorable, for example, to saturate the alcohol withgaseous HCl, or to re-saturate during the reaction.

Alternatively, the exchange of fluorine for alkoxy in the 2-position ofthe pyridyl substituent can be carried out at an earlier stage in thesynthesis, for example at the stage of the oxime ketones or the amineketones. In these cases, the reactions proceed under conditionscomparable to those just described for intermediate Ib (22c).

Processes E, F and G:

The compounds according to the invention in which R³ is an amidosubstituent (R³=NR⁷COR¹⁰) are, firstly, prepared from the4(5)-(2-halopyridin-4-yl)-substituted 2-thioimidazoles. The process(process E) is illustrated in scheme 6.1 using the 2-benzoylamido(R³=NH—COPh) where R¹=p-fluorophenyl as an example. Secondly, after thehydrolysis of the amides to the amine-substituted (R³=NR⁷H, NHR¹⁰)2-thioimidazoles and their re-acylation or derivatization to amides,ureas and urethanes, further amido substituents may be obtained (processF). This is illustrated in scheme 6.2. Thirdly, 2-aminopyridineprecursor compounds may be obtained from 4(5)-(2-halopyridin-4-yl)compounds via the 4(5)-(2-azidopyridin-4-yl) compounds (process G). Inthis variant, the halogen is substituted nucleophilically by an alkalimetal azide, and the azide group is then converted by reduction methodsinto the amino group, see scheme 6.3.

Process H:

This interesting variant also allows access to alkylated amines fromaldehyde and ketone precursors. If the conversion of the azide groupinto the amino group is carried out under hydrogenation conditions usinga hydrogenation catalyst in the presence of these aldehydes and ketones,alkylated amines where R³=NHCH₂—B or NHCH(alkyl)-B are obtained (processH, scheme 6.4). The same result is obtained when the azide is cleavedwith a phosphine to give the phosphimide, and these imides obtainedafter an aza-Wittig reaction with an aldehyde (or ketone) are reduced tothe amines using complex hydrides (process H, scheme 6.5).

The starting materials (Ib) can be prepared by the processes describedabove.

The reaction is expediently carried out in the amide in question, whichis preferably employed in an amount of from 5 to 20 mole equivalents permole equivalent of the compound (Ib). The reaction temperature isgenerally in the range from 100 to 200° C. If desired, it is alsopossible to use an inert solvent, such as dioxane, dimethylformamide,diethylacetamide, tetraethylurea, methylpyrrolidone, etc., andappropriate additives, such as alkali metal carbonates or monovalentcopper halides (to neutralize acid equivalents released or to catalyzethe elimination of halogen).

The 2-aminopyridine compounds can be obtained from 2-amidoacylpyridinesby hydrolysis (6.2) or else by azide substitution of the 2-fluorocompounds and subsequent reduction of the 2-azidopyridines (6.3), forexample by hydrogenation on palladium-on-carbon in alcoholic solvents.

Further conversions of the amines obtained (Ik, Id) by derivatizationare possible (process F). What is used are reactions of the amines Idand Ik both with acid anhydrides and acid chlorides to give furtheramides, and also reactions with chloroformic esters to give urethanes,with isocyanates to give ureas and with acyl isocyanates to giveacylureas. These formations of derivatives are illustrated in scheme 7.

In vitro and in vivo, the compounds according to the invention showimmunomodulating and cytokine-release inhibiting action. Cytokines areproteins such as TNF-α and IL-β which play an important role in numerousinflammatory disorders. The compounds according to the invention are, byvirtue of their cytokine-release-inhibiting action, suitable fortreating disorders which are associated with a disturbance of the immunesystem. They are suitable, for example, for treating autoimmunedisorders, cancer, rheumatoid arthritis, gout, septic shock,osteoporosis, neuropathic pain, the spread of HIV, HIV dementia, viralmyocarditis, insulin-dependent diabetes, periodontal disorders,restenosis, alopecia, T-cell depletion associated with HIV infections orAIDS, psoriasis, acute pancreatitis, rejection reactions of allogenictransplants, allergic pneumonia, arteriosclerosis, multiple sclerosis,cachexia, Alzheimer's disease, stroke, ictus, colitis ulcerosa, morbusCrohn, inflammatory bowel disease (IBD), ischemia, congestive heartfailure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-Barresyndrome, systemic lupus erythematodes, adult respiratory distresssyndrome (ARDS) and respiratory distress syndrome.

The compounds according to the invention can be administered either asindividual therapeutically active compounds or as mixtures with othertherapeutically active compounds. The compounds can be administered ontheir own; in general, however, they are formulated and administered inthe form of pharmaceutical compositions, i.e. as mixtures of the activecompounds with suitable pharmaceutical carriers or diluents. Thecompounds or compositions can be administered orally or parenterally;preferably, they are administered in oral dosage forms.

The type of pharmaceutical composition or carrier or diluent depends onthe desired administration form. Oral compositions, for example, can bepresent as tablets or capsules and may comprise customary excipients,such as binders (for example syrup, gum arabic, gelatin, sorbitol,tragacanth or polyvinylpyrrolidone), fillers (for example lactose,sugar, cornstarch, calcium phosphate, sorbitol or glycerol), glidants(for example magnesium stearate, talc, polyethylene glycol or silica),disintegrants (for example starch) or wetting agents (for example sodiumlauryl sulfate). Liquid oral preparations can assume the form of aqueousor oily suspensions, solutions, emulsions, syrups, elixirs or sprays andthe like. They can also be present as a dry powder which isreconstituted using water or another suitable carrier. Such liquidpreparations may comprise customary additives, for example suspendingagents, flavors, diluents or emulsifiers. For parenteral administration,it is possible to use solutions or suspensions with customarypharmaceutical carriers.

The compounds or compositions according to the invention can beadministered to mammals (man or animal) in a dose of from about 0.5 mgto 100 mg per kg of body weight per day. They may be administered in oneindividual dose or in a plurality of doses. The activity spectrum of thecompounds as inhibitors of cytokine release was examined using the testsystems below, as described by C. Donat and S. Laufer in Arch. Pharm.Pharm. Med. Chem. 333, Suppl. 1, 1-40. 2000.

In Vitro Test with Human Whole Blood

The test substance is added to samples of human potassium-EDTA wholeblood (of 400 μl each) and the samples are preincubated in a CO₂incubator (5% CO₂; 95% moisture-saturated air) at 37° C. for 15 min. Thesamples are then stimulated with 1 μg/ml of LPS (E. coli 026:B6) at 37°C. in a CO₂ incubator (5% CO₂; 95% moisture-saturated air) for 4 hours.The reaction is stopped by placing the samples on ice, adding DPBSbuffer and then centrifuging at 1000 g for 15 min. The amount of IL-1βand TNFα in the plasma supernatant is then determined by ELISA.

In Vitro Test with PBMCs

-   1) The mononuclear cells (PBMCS) from human potassium-EDTA whole    blood, diluted 1:3, are isolated by density gradient centrifugation    (Histopaque®-1.077). The cells are washed twice with DPBS buffer,    resuspended in macrophage SFM medium and adjusted to a cell count of    1×10⁶ cells/ml.-    The resulting PBMCs suspension (samples of in each case 390 μl) and    the test substance are preincubated at 37° C. in a CO₂ incubator (5%    CO₂; 95% moisture-saturated air) for 15 min. The samples are then    stimulated with in each case 1 μl/ml of LPS (E. coli 026:B6) at    37° C. in a CO₂ incubator (5% CO₂; 95% moisture-saturated air) for 4    hours. The reaction is stopped by placing the samples on ice, adding    DPBS buffer and then centrifuging at 15 880 g for 12 min. The amount    of IL-1β and TNFα in the plasma supernatant is then determined by    ELISA.    2) Kinase Assay-   At 37° C., microtiter plates were coated for one hour with 50 μl of    ATF2 solution (20 μg/ml). The plates were washed three times with    water, and 50 μl of kinase mixture (50 mM tris-HCl, 10 mM MgCl₂, 10    mM β-glycerol phosphate, 10 μg/ml of BSA, 1 mM DTT, 100 μM ATP, 100    μM Na₃VO₄, 10 ng of activated p38a) with or without inhibitor were    added into the wells, and the plates were incubated at 37° C. for 1    hour. The plates were washed three times and then incubated with    phosphorus-ATF-2 antibody for one hour. The plates were once more    washed three times, and goat-antirabbit IgG labeled with alkaline    phosphatase was added at 37° C. for one hour (to fix    antibody-phosphorylated protein/substrate complex). The plates were    washed three times, and the alkaline phosphatase/substrate solution    (3 mM 4-NPP, 50 mM NaHCO₃, 50 mM MgCl₂, 100 μl/well) was added at    37° C. for 1.5 hours. Formation of 4-nitrophenolate was measured at    405 nm using a microtiter plate reader. The IC₅₀ values were    calculated.

The results of the in vitro tests are shown in table 1 below.

TABLE 1 Test results Whole Compound IC₅₀ (μM) IC₅₀ (μM) PBMCA K₅₀ (μM)blood No. p 38 TNF-α IL-1β TNF-α IL-1β 25a 2.2 0.35 25b 3.8 2.8 0.30 25c8.7 4.6 2.7 7.2 2.2 25d 1.9 0.15 25e 3.1 0.50 25f 0.65 0.63 0.108 25g0.79 0.64 0.056 25h 0.83 0.67 0.085 17.3 22.3 25i 0.95 0.50 0.15 14.813.3 25j 0.70 0.72 0.23 25k 0.13 0.34 0.030 25l 0.24 0.35 0.031 14.917.1 25m 0.38 0.16 0.039 2.7 0.99 25n 0.34 0.17 0.041 25o 0.90 0.370.044 26a 60.0 1.8 26b 4.2 40.5 2.9 26c 1.42 3.2 0.20 26d 0.38 2.7 0.04526e 21.0 0.18 27a 12.0 2.1 27b 9.3 6.9 2.45 27c 1.45 2.0 0.47 27d 0.270.91 0.040 10.0 15.7

The examples below illustrate the invention, without limiting it.

EXAMPLE 1

a) 4-(4-Fluorophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione

2-(4-Fluorophenyl)-3-hydroxy-3-pyridin-4-ylacrylonitrile (a1)

A mixture of ethyl isonicotinate (75.8 g; 0.5 mol) and4-fluorophenylacetonitrile (67.6 g; 0.5 mol) was added dropwise to asolution of metallic sodium (17.3 g; 0.7 mol) in absolute ethanol (250ml). The reaction mixture was stirred at 100° C. for 15 min. Thereaction mixture was then cooled in an ice bath, and 600 ml of distilledH₂O were added. When the mixture was acidified with concentrated HCl (90ml), the hydrochloride of a1 was obtained as yellow precipitate at pH 1.The precipitate was filtered off, washed with H₂O and dried underreduced pressure over P₂O₅. M.p. 226° C.

2-(4-Fluorophenyl)-1-pyridin-4-ylethanone (a2)

A solution of a1 (40.6 g; 0.15 mol) in 48% strength hydrobromic acid(130 ml) was stirred under reflux for 19 h. The mixture was cooled in anice bath, and the precipitate obtained (4-fluorophenylacetic acid) wasfiltered off and washed with H₂O. When the filtrate was neutralized withammonia water (80 ml) a2 was obtained as a dark-green precipitate whichwas filtered off, washed with H₂O and dried under reduced pressure overP₂O₅: light-gray/beige powder. M.p. 215° C.

2-(4-Fluorophenyl)-1-pyridin-4-ylethanone oxime (a3)

Sodium acetate (36.1 g; 0.44 mol) and hydroxylamine hydrochloride (22.0g; 0.32 mol) were introduced into a suspension of a2 (21.5 g; 0.1 mol)in 50% strength methanol (350 ml). The reaction mixture was stirredunder reflux for 1 h. When the clear solution was cooled in an ice bath,a3 was obtained as a beige precipitate which was filtered off, washedwith H₂O and dried under reduced pressure over P₂O₅.

M.p. 155° C.

2-(4-Fluorophenyl)-1-pyridin-4-ylethanone,O-[(4-methylphenyl)sulfonyl]oxime (a4)

Under an atmosphere of argon, a3 (10.1 g; 0.04 mol) was dissolved inabsolute pyridine (50 ml). The solution was cooled to 6° C., andtoluenesulfonyl chloride (10.1 g; 0.05 mol) was added a little at atime. After the addition had ended, the reaction mixture was stirred atroom temperature for 20 h. The mixture was then poured into 500 ml ofice-water. The precipitate (a4) was filtered off, washed with cold H₂Oand dried in a drying cabinet at 50° C. M.p. 201° C.

4-(4-Fluorophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione (1a)

Under an atmosphere of argon, a solution of a4 (10.0 g; 0.03 mol) inabsolute ethanol (56 ml) was cooled to 5° C., and a freshly preparedsolution of metallic sodium (0.75 g; 0.03 mol) in absolute ethanol (30ml) was added dropwise. The reaction mixture was stirred at 5° C. for 5h. After addition of diethyl ether (500 ml), stirring was continued for30 min. The precipitate (TosOH) was filtered off and washed with diethylether (4×50 ml). The combined ethereal phase was extracted with 10%strength hydrochloric acid (3×90 ml). The aqueous extract wasconcentrated to a volume of about 40 ml, and potassium thiocyanate (5.0g; 0.05 mol) was added. The reaction mixture was stirred under refluxfor 1 h. When the mixture was neutralized with 5% strength sodiumbicarbonate solution (270 ml), a5 was obtained as a beige precipitatewhich was filtered off, washed with H₂O and dried in a drying cabinet at60° C. Yield 5.6 g (79%); m.p. 382° C.

¹H-NMR (DMSO-d₆): δ (ppm) 7.1 (m, 2H, 4-F-Ph), 7.3 (m, 2H, 4-Pyr), 7.5(m, 2H, 4-F-Ph), 8.5 (m, 2H, 4-Pyr), 12.7 (d, 2H, exchangeable, NH)

The following compounds were obtained in a corresponding manner:

-   1b: 3-(4-fluorophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione-   1c: 4-(4-chlorophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione-   1d: 4-(4-bromophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione-   1e: 4-phenyl-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione

EXAMPLE 2

1-Chloromethyl-4-methylsulfanylbenzene (2)

4-Methylsulfanylbenzyl alcohol (30.5 g; 0.2 mol) was dissolved indichloromethane (180 ml). A solution of thionyl chloride (23.8 g; 0.2mol) in dichloromethane (120 ml) was added dropwise to the initialcharge, which was kept under reflux. The reaction mixture was stirredunder reflux for a further 2 h. The solution was cooled to roomtemperature, washed with H₂O (2×250 ml), dried over Na₂SO₄ andconcentrated. The oily residue (6) was purified by column chromatography(Al₂O₃, CH₂Cl₂).

¹H-NMR (CDCl₃): δ (ppm) 2.46 (s, 3H, CH₃), 4.5 (s, 2H, CH₂), 7.2-7.3 (q,4H, 4-MeS-Ph)

EXAMPLE 3

1-Chloromethyl-4-methanesulfinylbenzene (3)

A solution of 2 (17.3 g; 0.1 mol) in glacial acetic acid (150 ml) wascooled to 10° C. A solution of H₂O₂ (35% strength solution; 13.1 g; 0.13mol) in glacial acetic acid (50 ml) was added dropwise to the initialcharge. The reaction mixture was stirred at room temperature for 2 h.The mixture was cooled in an ice bath, ice (200 g) was added and themixture was neutralized with ammonia water (290 ml). The aqueous phasewas extracted with ethyl acetate (2×300 ml). The organic phase waswashed with H₂O (2×300 ml), dried over Na₂SO₄ and concentrated. Byscratching and cooling the oily residue, 3 was obtained in crystallineform.

¹H-NMR (CDCl₃): δ (ppm) 2.73 (s, 3H, CH₃), 4.6 (s, 2H, CH₂), 7.5 (d, 2H,4-MeS(O)-Ph), 7.6 (d, 2H, 4-MeS(O)-Ph)

EXAMPLE 4

1-Chloromethyl-4-methanesulfonylbenzene (4)

m-Chloroperbenzoic acid (70%; 8.6 g; 0.04 mol) was introduced into asolution of 3 (3.0 g; 0.02 mol) in chloroform (50 ml). The reactionmixture was stirred under reflux for 4 h. The mixture was cooled to roomtemperature and filtered. The filtrate was washed with saturated NaHCO₃solution (2×) and dried over Na₂SO₄. After concentration of the organicphase, 8 remained as a crystalline white solid. M.p. 102° C.

¹H-NMR (CDCl₃): δ (ppm) 3.07 (s, 3H, CH₃), 4.6 (s, 2H, CH₂), 7.6 (d, 2H,4-MeSO₂-Ph), 7.9 (d, 2H, 4-MeSO₂-Ph)

EXAMPLE 5

Methyl 5-chlorosulfonyl-2-hydroxybenzoate (5a)

5a was prepared from methyl salicylate (10.0 g; 65.7 mmol) using themethod described in the synthesis of 5c.

¹H-NMR (CDCl₃): δ (ppm) 4.05 (s, 3H, CH₃), 7.18 (d, 1H, 8.9 Hz, C³—H),8.09 (dd, 1H, 2.5/9.0 Hz, C⁴—H), 8.57 (d, 1H, 2.5 Hz, C⁶—H), 11.55 (s,1H, exchangeable, phenol-OH)

Methyl 5-chloro-3-chlorosulfonyl-2-hydroxybenzoate (5b)

5b was prepared from methyl 5-chlorosalicylate (16.0 g; 85.7 mmol) usingthe method described in the synthesis of 5c.

¹H-NMR (CDCl₃): δ (ppm) 4.06 (s, 3H, CH₃), 8.11 (d, 1H, 2.7 Hz, C⁶—H),8.19 (d, 1H, 2.7 Hz, C⁴—H), 12.09 (s, 1H, exchangeable, phenol-OH)

Ethyl 3-chlorosulfanyl-4-methoxybenzoate (5c)

A solution of ethyl 4-methoxybenzoate (15.7 g; 87.2 mmol) in CCl₄ (60ml) was cooled to −15° C., and chlorosulfonic acid (17.5 ml; 263 mmol)was added dropwise over a period of 15 min, resulting in a temperatureincrease to −10° C. After the addition had ended, the reaction mixturewas stirred at room temperature for 2 h and then heated at 50° C. untilno more starting material could be detected by thin-layerchromatography. With ice-cooling and vigorous stirring, the reactionmixture was added to a suspension of ice (50 g) in CCl₄ (100 ml). Themixture was stirred vigorously for 3 min. The organic phase wasseparated off and the aqueous phase was extracted with CH₂Cl₂ (3×100ml). The combined organic extracts were washed with saturated NaClsolution (3×), dried over Na₂SO₄ and concentrated. Trituration of theoily brown residue with diethyl ether resulted in 5c precipitating as acrystalline white solid.

¹H-NMR (CDCl₃): δ (ppm) 1.41 (t, 3H, 7.1 Hz, CH₃), 4.14 (s, 3H, CH₃),4.42 (q, 2H, 7.1 Hz, CH₂), 7.18 (d, 1H, 8.8 Hz, C⁵—H), 8.37 (dd, 1H,2.1/8.8 Hz, C⁶—H), 8.63 (d, 1H, 2.1 Hz, C²—H)

EXAMPLE 6

2-Hydroxy-5-mercaptobenzoic acid (6a)

6a was prepared from 5a (0.50 g; 2.0 mmol) using the method described inthe synthesis of 7c, without alkylation with dimethyl sulfate

¹H-NMR (DMSO-d₆): δ (ppm) 5.39 (bs, 1H, exchangeable, carboxyl-OH), 6.90(d, 1H, 8.7 Hz, C³—H), 7.45 (dd, 1H, 2.5/8.6 Hz, C⁴—H), 7.75 (d, 1H, 2.5Hz, C⁶—H), phenol-OH not visible

EXAMPLE 7

2-Hydroxy-5-methylsulfanylbenzoic acid (7a)

7a was prepared from 5a (10.0 g; 40.0 mmol) using the method describedin the synthesis of 7c.

¹H-NMR (CDCl₃): δ (ppm) 2.48 (s, 3H, CH₃), 6.97 (d, 1 H, 8.7 Hz, C³—H),7.51 (dd, 1H, 2.5/8.7 Hz, C⁴—H), 6.97 (d, 1H, 8.7 Hz, C³—H), 7.87 (d,1H, 2.4 Hz, C⁶—H), 10.26 (bs, 1H, phenol-OH), CO₂H not visible

5-Chloro-2-hydroxy-3-methylsulfanylbenzoic acid (7b)

7b was prepared from 5b (13.0 g; 45.6 mmol) using the method describedin the synthesis of 7c.

¹H-NMR (DMSO-d₆): δ (ppm) 2.47 (s, 3H, CH₃), 7.33 (d, 1H, 2.4 Hz, C⁶—H),7.52 (d, 1H, 2.4 Hz, C⁴—H), phenol-OH and CO₂H not visible

4-Methoxy-3-methylsulfanylbenzoic acid (7c)

Triphenylphosphine (20.5 g; 78.2 mmol) was introduced a little at a timeinto a solution of 5c (5.1 g; 18.3 mmol) in toluene (50 ml). Thereaction mixture was stirred at room temperature for 4.5 h. Theprecipitate (triphenylphosphine oxide) was filtered off, and the yellowfiltrate was extracted with 10% strength aqueous sodium hydroxidesolution (4×). Dimethyl sulfate (2 ml) was added to the combined aqueousextract, and the reaction mixture was stirred at room temperature for 2h. The precipitate obtained was dissolved by heating to refluxtemperature. The clear solution was cooled and adjusted to pH 1 using20% strength hydrochloric acid. The precipitate (7c) was filtered off,washed with H₂O and dried under reduced pressure over CaCl₂.

¹H-NMR (CD₃OD): δ (ppm) 2.43 (s, 3H, S—CH₃), 3.93 (s, 3H, O—CH₃), 6.98(d, 1H, 8.4 Hz, C⁵—H), 7.79-7.86 (m, 2H, C²—/C⁶—H)

4-Hydroxy-3-methylsulfanylbenzoic acid (7d)

A suspension of 7c (0.5 g; 2.5 mmol) in glacial acetic acid/48% strengthhydrobromic acid (1+1, 7 ml) was stirred under reflux for 6 h. Thereaction mixture was cooled, added to H₂O (20 ml) and adjusted to pH 2using 10% strength Na₂CO₃ solution. The aqueous solution was extractedwith diethyl ether (4×20 ml). The combined organic extract was washedwith saturated NaCl solution (2×), dried over Na₂SO₄ and concentrated.On standing at room temperature, the off-brown oily residue (7d)crystallized out. The crystals were triturated with H₂O, filtered offand dried.

¹H-NMR (CDCl₃): δ (ppm) 2.38 (s, 3H, CH₃), 7.05 (d, 1 H, 8.5 Hz, C⁵—H),8.02 (dd, 1H, 2.2/8.5 Hz, C⁶—H), 8.29 (d, 1H, 2.2 Hz, C²—H), phenol-OHand CO₂H not visible

EXAMPLE 8

2-Hydroxymethyl-4-methylsulfanylphenol (8a)

8a was prepared from 7a (1.5 g; 8.1 mmol) using the method described inthe synthesis of 8c.

¹H-NMR (CDCl₃): δ (ppm) 2.42 (s, 3H, CH₃), 4.79 (s, 2H, CH₂), 6.81 (d,1H, 8.4 Hz, C⁶—H), 7.01 (d, 1H, 2.1 Hz, C³—H), 7.17 (dd, 1H, 2.3/8.4 Hz,C³—H), OH not visible

4-Chloro-2-hydroxymethyl-6-methylsulfanylphenol (8b)

8b was prepared from 7b (2.2 g; 10.1 mmol) using the method described inthe synthesis of 8c.

¹H-NMR (DMSO-d₆): δ (ppm) 2.38 (s, 3H, CH₃), 4.52 (s, 2H, CH₂), 5.3-5.5(bs, 1H, exchangeable, hydroxyl-OH), 7.03 (d, 1H, 2.6 Hz, C⁵—H), 7.11(d, 2.4 Hz, C³—H), 9.02 (bs, 1H, exchangeable, phenol-OH)

4-Hydroxymethyl-2-methylsulfanylphenol (8c)

With ice-cooling, a solution of 7d (1.37 g; 7.4 mmol) in abs.tetrahydrofuran (THF; 15 ml) was added to a suspension of 95% pureLiAlH₄ (0.55 g; 14 mmol) in absolute THF (10 ml) in a three-necked flask(which had been dried by heating and flushed with argon) such that therewas only a moderate evolution of gas. After the addition had ended,cooling was removed and the reaction mixture was stirred at roomtemperature for 30 min and at 55-65° C. for a further 21 h. Withice-cooling, ice-water was added to the reaction mixture. Theprecipitate of Al(OH)₃ was dissolved by adding 10% strength sulfuricacid, and the aqueous-acidic solution (pH 1) was extracted with diethylether (3×50 ml). The combined ethereal extract was extracted with 10%strength aqueous sodium hydroxide solution (2×25 ml). The combinedsodium hydroxide solution was neutralized with 20% strength hydrochloricacid. The precipitate (8c) was filtered off, washed with H₂O and dried.A further charge of 8c was obtained by extraction of the neutral aqueoussolution with diethyl ether. The ethereal extract was washed withsaturated NaCl solution, dried over Na₂SO₄ and concentrated: crystallinewhite solid.

¹H-NMR (CDCl₃): δ (ppm) 2.34 (s, 3H, CH₃), 4.60 (s, 2H, CH₂), 6.97 (d,1H, 8.3 Hz, C⁶—H), 7.24 (dd, 1H, 2.0/8.4 Hz, C⁵—H), 7.50 (d, 1H, 2.0 Hz,C³—H), OH not visible

EXAMPLE 9

2-Hydroxy-5-methylsulfanylbenzaldehyde (9a)

The title compound was obtained as a byproduct in the synthesis of 8a.

¹H-NMR (CDCl₃): δ (ppm) 2.48 (s, 3H, CH₃), 6.96 (d, 1H, 9.8 Hz, C³—H),7.48-7.54 (m, 2H, C⁴—/C⁶—H), 9.87 (s, 1H, exchangeable, OH), 10.91 (s,1H, aldehyde-H)

EXAMPLE 10

4-(3-Chloroethyl)benzenesulfonyl chloride (10a)

With ice-cooling, (2-chloroethyl)benzene (14.0 g; 0.1 mol) was addeddropwise over a period of 40 min to chlorosulfonic acid (72 g). Thebrown solution was stirred at room temperature for 24 h, cooled in anice-bath and, a little at a time, added to ice, where a viscous materialseparated out that could not be filtered. The aqueous solution wasextracted with ethyl acetate (3×). The combined organic extract waswashed with 10% strength NaHCO₃ solution, dried over Na₂SO₄ andconcentrated. The oily residue was taken up in tert-butyl methylether/petroleum ether. The solution was scratched with a glass rod andcooled. The white crystals were filtered off and dried. Further reactionproduct was obtained from the mother liquor. The crude product was usedwithout further purification for the synthesis of 11a.

¹H-NMR (CDCl₃): δ (ppm) 3.20 (t, 2H, 6.8 Hz, CH₂), 3.79 (t, 2H, 6.8 Hz,CH₂), 7.46-7.53 (m, 2H, phenyl), 7.97-8.04 (m, 2H, phenyl)

4-(3-Chloropropyl)benzenesulfonyl chloride (10b)

10b was prepared from (3-chloropropyl)benzene (15.5 g; 0.1 mol) usingthe method described in the synthesis of 10a. The crude product was usedwithout further purification for the synthesis of 11b.

MS: m/z (%) 253 (90. M⁺), 217 (100. M⁺—Cl), 189 (35), 153 (97,M⁺—SO₂Cl), 125 (94), 119 (65, phenylpropylcarbenium⁺), 91(90), 77 (29,phenyl⁺)

EXAMPLE 11

1-(3-Chloroethyl)-4-methylsulfanylbenzene (11a)

11a was prepared from 10a (12.0 g; 0.05 mol) using the method describedin the synthesis of 11b.

¹H-NMR (CDCl₃): δ (ppm) 2.47 (s, 3H, CH₃), 3.02 (t, 2H, 7.4 Hz, CH₂),3.68 (t, 2H, 7.5 Hz, CH₂), 7.11-7.25 (m, 4H, phenyl)

1-(3-Chloropropyl)-4-methylsulfanylbenzene (11b)

At room temperature, a solution of 10b (12.7 g; 5.0 mmol) in diethylether (75 ml) was added dropwise over a period of 2.5 h to a suspensionof LiAlH₄ (2.9 g; 7.6 mmol) in diethyl ether (50 ml). After the additionhad ended, the reaction mixture was stirred at room temperature and withoccasional addition of LiAlH₄ until no more starting material could bedetected by thin-layer chromatography (2.5 h). With ice-cooling, ice wasintroduced into the reaction mixture, and the aqueous phase wasacidified with 10% hydrochloric acid (pH 1). The organic phase wasremoved and the aqueous phase was extracted with diethyl ether (3×). Thecombined organic extract was washed with 10% strength aqueous sodiumhydroxide solution (4×50 ml) until it was virtually colorless. Dimethylsulfate (9.0 g; 7.0 mmol) was added to the combined sodium hydroxideextract, and the mixture was stirred at room temperature for 16.5 h. Theoily sediment was taken up in diethyl ether. The organic phase wasseparated off and the aqueous phase was again extracted with diethylether (2×). The combined organic extract was dried over Na₂SO₄ andconcentrated. The brown oily residue was subjected to a kugelrohrdistillation (0.2 mbar, 250° C.).

¹H-NMR (CDCl₃): δ (ppm) 2.01-2.11 (m, 2H, CH₂), 2.46 (s, 3H, CH₃), 2.73(t, 2H, 7.1 Hz, CH₂), 3.51 (t, 2H, 6.5 Hz, CH₂), 7.09-7.25 (m, 4H,phenyl)

EXAMPLE 12

1-(2-Chloroethyl)-4-methanesulfinylbenzene (12a)

With cooling, a 35% strength solution of H₂O₂ (0.9 g; 9.3 mmol) wasadded to a solution of 11a (1.5 g; 8.0 mmol) in glacial acetic acid (20ml). After the addition had ended, the reaction mixture was stirred atroom temperature for 2.5 h diluted with cooling with ice-water andadjusted to pH 8 using 25% strength ammonia water. The oily whitesediment was taken up in diethyl ether and the aqueous phase wasextracted with diethyl ether (3×). The combined organic extract wasdried over Na₂SO₄ and concentrated.

¹H-NMR (CDCl₃): δ (ppm) 2.73 (s, 3H, CH₃), 3.14 (t, 2H, 7.1 Hz, CH₂),3.76 (t, 2H, 7.1 Hz, CH₂), 7.38-7.42 (m, 2H, phenyl), 7.60-7.64 (m, 2H,phenyl)

1-(3-Chloropropyl)-4-methanesulfinylbenzene (12b)

12b was prepared from 11b (2.0 g; 10.0 mmol) using the method describedin the synthesis of 12a. M.p.: 46° C.

General methods for preparing the compounds of the formula I:

Preparation of the 2-arylalkyl- or alkylsulfanylimidazoles (GeneralMethod A)

A suspension of the respective imidazole-2-thione (1 equivalent), of therespective base (1.2 equivalents) and of the respective arylalkyl oralkyl halide (1 equivalent) in ethanol/THF (8+2) was stirred underreflux until no more imidazole-2-thione could be detected by thin-layerchromatography. The reaction mixture was cooled to room temperature andfiltered. The filtrate, which in most cases was of red/orange color, wasconcentrated, and the residue was purified by column chromatography,recrystallization or trituration. The compounds 13a-c, 14a-c and 17a-mwere prepared in this manner.

Preparation of the 2-benzylsulfanylimidazoles Having PhenolicFunctionality in the Radical R² (General Method B)

By addition of 10% strength hydrochloric acid (10-15 drops), theimidazole-2-thione 1a (1 equivalent) was dissolved in glacial aceticacid (5 ml). The respective benzyl alcohol (1 equivalent) was added tothe initial charge, which had a light-yellow color, and the reactionmixture was stirred at a suitable temperature (temperature/time) untilno more 1a could be detected by thin-layer chromatography. In the caseof the sulfoxides 18g-i, a 35% strength solution of H₂O₂ was added, andthe reaction mixture was stirred at room temperature for a further 4 h.The reaction mixture was diluted with H₂O (5 ml) and adjusted to pH 8using 25% strength ammonia water. The precipitate was filtered off andwashed with water. The crude product was purified by columnchromatography, recrystallization or trituration. Theimidazol-2-ylsulfanylmethylphenols 18a-i were prepared in this manner.

Preparation of N-substituted 2-aminopyridines (General Method C)

Under argon, the respective 5-(2-halopyridin-4-yl)imidazole (1equivalent) was suspended in the respective amine (about 10equivalents). The reaction mixture was stirred at the respectivetemperature until no more starting material could be detected bythin-layer chromatography. The reaction mixture was cooled to roomtemperature and taken up in 10% citric acid which had been adjustedbeforehand to pH 5 using 20% strength NaOH. The aqueous emulsion wasextracted with ethyl acetate (3×). The combined organic extract waswashed with 10% strength citric acid/pH 5 (1×), 10% strength Na₂CO₃solution (2×) and saturated NaCl solution (1×), dried over Na₂SO₄ andconcentrated. The oily residue was separated by column chromatography.The aminopyridines 25f-p, 26c-e and 27c-d were prepared in this manner.

EXAMPLE 13

3-[5-(4-Fluorophenyl)-2-(4-methylsulfanylbenzylsulfanyl)-3H-imidazol-4-yl]-pyridine(13a)

Using the general method A, the title compound was obtained from 1b(0.42 g; 1.5 mmol) and 2 (0.25 g; 1.4 mmol) after a reaction time of 4.5hours and separation by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH9+1).

M.p. 163° C.

IR (ATR) (attenuated total reflection) 1506, 1493, 1222 (C—F), 837, 806cm⁻¹

¹H-NMR (DMSO-d₆ ): δ (ppm) 2.45 (s, 3H, CH₃), 4.38 (s, 2H, CH₂),7.19-7.49 (m, 10H, 3-Pyr, 4-F-Ph and 4-MeS-Ph), 7.78-7.82 (m, 1H,3-Pyr), 8.45-8.47 (m, 1H, 3-Pyr), 8.61 (s, 1H, 3-Pyr), 12.71 (bs, 1H,exchangeable, NH)

3-[5-(4-Fluorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl]-pyridine(13b).

Using the general method A, the title compound was obtained from 1b(0.42 g; 1.5 mmol) and 3 (0.27 g; 1.5 mmol) after a reaction time of 8hours and separation by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH9+1).

M.p. 127° C.

IR (ATR): 1506, 1222 (C—F), 1027 (S═O), 1013, 838, 811 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 3.19 (s, 3H, CH₃), 4.46 (s, 2H, CH₂),7.16-7.46 (m, 5H, 3-Pyr and 4-F-Ph), 7.56-7.66 (m, 4H, 4-MeS(O)-Ph),7.72-7.81 (m, 1H, 3-Pyr), 8.41-8.62 (m, 2H, 3-Pyr), 12.77 (bs, 1H,exchangeable, NH)

3-[5-(4-Fluorophenyl)-2-(4-methanesulfonylbenzylsulfanyl)-3H-imidazol-4-yl]-pyridine(13c).

Using the general method A, the title compound was obtained from 1b(0.42 g; 1.5 mmol) and 4 (0.29 g; 1.43 mmol) and with addition of Na₂CO₃(0.43 g; 4.1 mmol) after a reaction time of 6.5 hours and triturationwith hot ethyl acetate. M.p. 129° C.

IR (ATR): 1506, 1296 (SO2), 1222 (C—F), 1145 (SO2), 1089, 839, 812 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 3.19 (s, 3H, CH₃), 4.50 (s, 2H, CH₂),7.17-7.45 (m, 5H, 3-Pyr and 4-F-Ph), 7.64-7.90 (m, 5H, 3-Pyr and4-MeSO₂-Ph), 8.43-8.61 (m, 2H, 3-Pyr), 12.78 (bs, 1H, exchangeable, NH)

EXAMPLE 14

4-[5-(4-Chlorophenyl)-2-(4-methylsulfanylbenzylsulfanyl)-3H-imidazol-4-yl]-pyridine(14a)

Using the general method A, the title compound was obtained from 1c(0.26 g; 0.9 mmol) and 6 (0.15 g; 0.87 mmol) and with addition of Na₂CO₃(two spatula tips) after a reaction time of 6.5 hours and separation bycolumn chromatography (SiO₂ 60, CH₂Cl₂/EtOH 9+1). M.p. 236° C.

IR (ATR): 1600, 1492, 1094, 1005, 968, 829, 684 (C—Cl), 561 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 2.44 (s, 3H, CH₃), 4.38 (s, 2H, CH₂),7.18-7.56 (m, 10H, 4-Pyr, 4-Cl-Ph and 4-MeS-Ph), 8.45-8.55 (m, 2H,4-Pyr), 12.86 (bs, 1H, exchangeable, NH)

4-[5-(4-Chlorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl]-pyridine(14b)

Using the general method A, the title compound was obtained from 1c(0.26 g; 0.9 mmol) and 3 (0.16 g; 0.85 mmol) and with addition of Na₂CO₃after a reaction time of 6.5 hours and separation by columnchromatography (SiO₂ 60, CH₂Cl₂/EtOH 9+1). M.p. 224° C.

IR (ATR): 1600, 1510, 1490, 1033 (S═O), 1001, 967, 829, 677 cm⁻¹ (C—Cl)

¹H-NMR (DMSO-d₆): δ (ppm) 2.70 (s, 3H, CH₃), 4.47 (s, 2H, CH₂),7.31-7.65 (m, 10H, 4-Pyr, 4-Cl-Ph and 4-MeS(O)-Ph), 8.44-8.54 (m, 2H,4-Pyr), 12.87 (bs, 1H, exchangeable, NH)

4-[5-(4-Chlorophenyl)-2-(4-methanesulfonylbenzylsulfanyl)-3H-imidazol-4-yl]-pyridin(14c)

Using the general method A, the title compound was obtained from 1c(0.26 g; 0.9 mmol) and 4 (0.18 g; 0.9 mmol) and with addition of Na₂CO₃(two spatula tips) after a reaction time of 6.5 hours and separation bycolumn chromatography (SiO₂ 60, CH₂Cl₂/EtOH 9+1). M.p. 232° C.

IR (ATR): 1603, 1490, 1300 (SO2), 1141 (SO2), 1086, 1002, 952, 829, 681(C—Cl), 550 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 3.19 (s, 3H, CH₃), 4.52 (s, 2H, CH₂),7.32-7.58 (m, 6H, 4-Pyr and 4-Cl-Ph), 7.67 (d, 2H, 8.2 Hz, 4-MeSO₂-Ph),7.88 (d, 2H, 8.3 Hz, 4-MeSO₂-Ph, 8.45-8.55 (m, 2H, 4-Pyr), 12.89 (bs,1H, exchangeable, NH)

EXAMPLE 15

4-[5-(4-Bromophenyl)-2-(4-methylsulfanylbenzylsulfanyl)-3H-imidazol-4-yl]-pyridine(15a)

Using the general method A, the title compound was obtained from 1d(0.25 g; 0.75 mmol) and 2 (0.13 g; 0.72 mmol) after a reaction time of 5hours and separation by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH9+1).

IR (ATR): 1600, 1517, 1490, 1089, 1069, 1003, 968, 826 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 2.43 (s, 3H, CH₃), 4.36 (s, 2H, CH₂),7.16-7.87 (m, 10H, 4-Pyr, 4-Br-Ph and 4-MeS-Ph), 8.45-8.55 (m, 2H,4-Pyr), 12.90 (bs, 1H, exchangeable, NH)

4-[5-(4-Bromophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl]-pyridine(15b)

Using the general method A, the title compound was obtained from 1d(0.25 g; 0.75 mmol) and 3 (0.14 g; 0.72 mmol) after a reaction time of10 hours and separation by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH9+1).

M.p. 222° C.

IR (ATR): 1604, 1487, 1035 (S═O), 1010, 1000, 966, 822 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 2.71 (s, 3H, CH₃), 4.48 (s, 2H, CH₂),7.40-7.62 (m, 20H, 4-Pyr, 4-Br-Ph and 4-MeS(O)-Ph), 8.49-8.57 (m, 2H,4-Pyr), 12.90 (bs, 1H, exchangeable, NH)

4-[S-(4-Bromophenyl)-2-(4-methanesulfonylbenzylsulfanyl)-3H-imidazol-4-yl]-pyridine(15c)

Using the general method A, the title compound was obtained from 1d(0.25 g; 0.75 mmol) and 4 (0.15 g; 0.72 mmol) after a reaction time of 5hours and separation by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH9+1).

M.p. 226° C.

IR (ATR): 1605, 1318, 1303 (SO2), 1145 (SO2), 1003, 967, 957, 827, 822cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 3.18 (s, 3H, CH₃), 4.50 (s, 2H, CH₂),7.33-7.89 (m, 10H, 4-Pyr, 4-Br-Ph and 4-MeSO₂-Ph), 8.45-8.54 (m, 2H,4-Pyr), 12.91 (bs, 1H, exchangeable, NH)

EXAMPLE 16

4-[2-(4-Methylsulfanylbenzylsulfanyl)-5-phenyl-3H-imidazyl-4-yl]pyridine(16a)

Using the general method A, the title compound was obtained from 1e(0.38 g; 1.5 mmol) and 2 (0.25 g; 1.4 mmol) after a reaction time of5.75 hours and separation by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH9+1).

M.p. 213° C.

IR (ATR): 1601, 1491, 1417, 1094, 1004, 967, 828, 771, 700 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 2.44 (s, 3H, CH₃), 4.38 (s, 2H, CH₂),7.18-7.58 (m, 11H 4-Pyr, Ph and 4-MeS-Ph), 8.44-8.47 (m, 2H, 4-Pyr),12.82 (bs, 1H, exchangeable, NH)

4-[2-(4-Methanesulfinylbenzylsulfanyl)-5-phenyl-3H-imidazol-4-yl]pyridine(16b)

Using the general method A, the title compound was obtained from 1e(0.38 g; 1.5 mmol) and 3 (0.27 g; 1.43 mmol) after a reaction time of5.5 hours and separation by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH9+1).

M.p. 189° C.

IR (ATR): 1603, 1494, 1051 (S═O), 1003, 833, 701 cm−1

¹H-NMR (DMSO-d₆): δ (ppm) 2.71 (s, 3H, CH₃), 4.48 (s, 2H, CH₂),7.32-7.52 (m, 7H, 4-Pyr and Ph), 7.57-7.67 (m, 4H, 4-MeS(O)-Ph),8.45-8.54 (m, 2H, 4-Pyr), 12.84 (bs, 1H, exchangeable, NH)

4-[2-(4-Methanesulfonylbenzylsulfanyl)-5-phenyl-3H-imidazol-4-yl]pyridine(16c)

Using the general method A, the title compound was obtained from 1e(0.38 g; 1.5 mmol) and 4 (0.29 g; 1.43 mmol) after a reaction time of4.25 hours and separation by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH9+1).

M.p. 247° C.

IR (ATR): 1602, 1298 (SO2), 1145 (SO2), 1006, 953, 827, 775, 701 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 3.21 (s, 3H, CH₃), 4.54 (s, 2H, CH₂),7.31-7.58 (m, 7H, 4-Pyr and Ph), 7.70 (d, 2H, 8.3 Hz, 4-MeSO₂-Ph), 7.91(d, 2H, 8.3 Hz, 4-MeSO₂-Ph), 8.45-8.59 (m, 2H, 4-Pyr), 12.87 (bs, 1H,exchangeable, NH)

EXAMPLE 17

4-{5-(4-Fluorophenyl)-2-[2-(4-methanesulfinylphenyl)ethylsulfanyl]-1H-imidazol-4-yl}pyridine(17a)

Using the general method A, the title compound was obtained from 1a(0.25 g; 0.9 mmol) and 12a (0.22 g; 1.1 mmol) and with addition ofNa₂CO₃ (1 spatula tip) and a catalytic amount of NaI after a reactiontime of 50 hours and purification by column chromatography (SiO₂ 60,CH₂Cl₂/EtOH 9+1).

M.p. 177° C.

IR (ATR): 1221 (C—F), 1032 cm⁻¹ (S═O)

¹H-NMR (DMSO-d₆): δ (ppm) 2.71 (s, 3H, CH₃), 3.06-3.13 (m, 2H, CH₂),3.42-3.49 (m, 2H, CH₂), 7.25-7.65 (m, 1OH, 4-Pyr, 4-F-Ph and4-MeS(O)-Ph), 8.40-8.58 (m, 2H, 4-Pyr), 12.80 (bs, 1H, exchangeable, NH)

4-{5-(4-Fluorophenyl)-2-[2-(4-methanesulfinylphenyl)propylsulfanyl]-1H-imidazol-4-yl}pyridine(17b)

Using the general method A, the title compound was obtained from 1a(0.25 g; 0.9 mmol) and 12b (0.22 g; 1.0 mmol) and with addition ofNa₂CO₃ (1 spatula tip) and a catalytic amount of NaI after a reactiontime of 40 hours and purification by column chromatography (SiO₂ 60,CH₂Cl₂/EtOH 9+1).

M.p. 142° C.

IR (ATR): 1222 (C—F), 1043 cm⁻¹ (S═O)

¹H-NMR (DMSO-d₆): δ (ppm) 1.95-2.09 (m, 2H, CH₂), 2.71 (s, 3H, CH₃),2.82 (t, 2H, 7.4 Hz, CH₂), 3.15 (t, 2H, 7.0 Hz, CH₂), 7.25-7.62 (m, 10H,4-Pyr, 4-F-Ph and 4-MeS(O)-Ph, 8.46-8.49 (m, 2H, 4-Pyr), 12.86 (bs, 1H,exchangeable, NH)

4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-1H-imidazol-4-yl]pyridine (17c)

Using the general method A, the title compound was obtained from 1a(0.28 g; 1.0 mmol) and 1-chloromethylbenzene (0.13 g; 1.0 mmol) after areaction time of 6 hours and trituration with MeOH. M.p. 223° C.

IR (ATR): 1233 cm⁻¹ (C—F)

¹H-NMR (DMSO-d₆): δ (ppm) 4.41 (s, 2H, CH₂), 7.23-7.51 (m, 11H, 4-Pyr,4-F-Ph and Bz), 8.44-8.47 (m, 2H, 4-Pyr), 12.82 (bs, 1H, exchangeable,NH)

4-[5-(4-Fluorophenyl)-2-phenethylsulfanyl-1 H-imidazol-4-yl]pyridine(17d)

Using the general method A, the title compound was obtained from 1a (0.5g; 1.9 mmol) and 2-chloroethylbenzene (0.28 g; 2.0 mmol) and withaddition of Na₂CO₃ (1 spatula tip) and a catalytic amount of NaI after areaction time of 70 hours and trituration with EtOH. M.p. 257° C.

IR (ATR): 1223 cm⁻¹ (C—F)

¹H-NMR (DMSO-d₆): δ (ppm) 2.99 (t, 2H, 7.4 Hz, CH₂), 3.40 (t, 2H, 7.5Hz, CH₂), 7.17-7.53 (m, 11H, 4-Pyr, 4-F-Ph and Bz), 8.44-8.46 (m, 2H,4-Pyr), NH not visible

4-[5-(4-Fluorophenyl)-2-(3-phenylpropylsulfanyl)-1H-imidazol-4-yl]pyridine(17e)

Using the general method A, the title compound was obtained from 1a (0.5g; 1.9 mmol) and 3-chloropropylbenzene (0.31 g; 2.0 mmol) and withaddition of Na₂CO₃ (1 spatula tip) and a catalytic amount of NaI after areaction time of 70 hours and trituration with EtOH. M.p. 183° C.

IR (ATR): 1226 cm⁻¹ (C—F)

¹H-NMR (DMSO-d₆): δ (ppm) 1.90-2.04 (m, 2H, CH₂), 2.72 (t, 2H, 7.4 Hz,CH₂), 3.12 (t, 2H, 7.0 Hz, CH₂), 7.18-7.51 (m, 11H, 4-Pyr, 4-F-Ph andBz), 8.37-8.44 (m, 2H, 4-Pyr), 12.82 (bs, 1H, exchangeable, NH)

[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanyl]acetonitrile(17f)

Using the general method A, the title compound was obtained from 1a (1.1g; 4.0 mmol) and chloroacetonitrile (0.30; 4.0 mmol) after a reactiontime of 18 hours and purification by column chromatography (SiO₂ 60,ethyl acetate).

M.p. 219° C.

IR (ATR): 2243 (CN), 1226 cm⁻¹ (C—F)

¹H-NMR (DMSO-d₆): δ (ppm) 4.32 (s, 2H, CH₂), 7.34-7.57 (m, 6H, 4-Pyr and4-F-Ph), 8.50-8.52 (m, 2H, 4-Pyr), 13.20 (bs, 1H, exchangeable, NH)

4-[5-(4-Fluorophenyl)-2-(naphthalen-1-ylmethylsulfanyl)-1H-imidazol-4-yl]-pyridine(17g)

Using the general method A, the title compound was obtained from 1a(0.28 g; 1.0 mmol) and 1-chloromethylnaphthol (0.18 g; 1.0 mmol) after areaction time of 6.5 hours and purification by column chromatography(SiO₂ 60, ethyl acetate). M.p. 364° C.

IR (ATR): 1225 cm⁻¹ (C—F)

¹H-NMR (DMSO-d₆): δ (ppm) 4.90 (s, 2H, CH₂), 7.25-7.62 (m, 10H, 4-Pyr,4-F-Ph and naphthyl), 7.80-7.98 (m, 2H, naphthyl), 8.20-8.23 (m, 1H,naphthyl), 8.48-8.52 (m, 2H, 4-Pyr), 12, (bs, 1H, exchangeable, NH)

4-[2-cyclohexylmethylsulfanyl-5-(4-fluorophenyl)-1H-imidazol-4-yl]pyridine(17h)

Using the general method A, the title compound was obtained from 1a(0.25 g; 0.9 mmol) and 1-chloromethylcyclohexane (0.18 g; 1.0 mmol) andwith addition of Na₂CO₃ (1 spatula tip) and a catalytic amount of NaIafter a reaction time of 47 hours and trituration with EtOH. M.p. 235°C.

IR (ATR): 2922, 2852 (c-Hex), 1222 cm⁻¹ (C—F)

¹H-NMR (DMSO-d₆): δ (ppm) 0.95-1.23 (m, 5H, cyclo-Hex), 1.51-1.85 (m,6H, cyclo-Hex), 3.06 (d, 2H, 6.7 Hz, CH₂), 7.22-7.51 (m, 6H, 4-Pyr and4-F-Ph), 8.43-8.45 (m, 2H, 4-Pyr), 12.76 (bs, 1H, exchangeable, NH)

4-[5-(4-Fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine (17i)

Using the general method A, the title compound was obtained from 1a(0.41 g; 1.5 mmol) and methyl iodide (0.27 g; 1.9 mmol) after a reactiontime of 8 hours and trituration with EtOH. M.p. 263° C.

IR (ATR): 1226 cm⁻¹ (C—F)

¹H-NMR (DMSO-d₆): δ (ppm) 2.61 (s, 3H, CH₃), 7.22-7.51 (m, 6H, 4-Pyr and4-F-Ph), 8.42-8.45 (m, 2H, 4-Pyr), NH not visible

4-[5-(4-Fluorophenyl)-2-(2-methylsulfanylbenzylsulfanyl)-1H-imidazol-4-yl]-pyridine(17j)

Using the general method A, the title compound was obtained from 1a(0.28 g; 1.0 mmol) and 1-chloromethyl-2-methylsulfanylbenzene (0.17 g;1.0 mmol) after a reaction time of 5.5 hours and purification by columnchromatography (SiO₂ 60, ethyl acetate). M.p. 223° C.

IR (ATR): 1228 cm⁻¹ (C—F)

¹H-NMR (CD₃OD): δ (ppm) 2.51 (s, 3H, CH₃), 4.44 (s, 2H, CH₂), 7.13-7.48(m, 10H, 4-Pyr, 4-F-Ph and 2-MeS-Ph), 8.43-8.46 (m, 2H, 4-Pyr)

4-[5-(4-Fluorophenyl)-2-(2-methanesulfinylbenzylsulfanyl)-1H-imidazol-4-yl]-pyridine(17k)

Using the general method A, the title compound was obtained from 1a(0.28 g; 1.0 mmol) and 1-chloromethyl-2-methanesulfinylbenzene (0.18 g;1.0 mmol) after a reaction time of 4 hours and recrystallization frommethanol/ethyl acetate (1+1). M.p. 205° C.

IR (KBr): 1213 (C—F), 1033 cm⁻¹ (S═O)

¹H-NMR (CD₃PD): δ (ppm) 2.87 (s, 3H, CH₃), 4.50 (d, 1H, 13.6 Hz, CH₂),4.62 (d, 1H, 13.6 Hz, CH₂), 7.24-7.33 (m, 2H, 4-F-Ph), 7.47-7.62 (m, 5H,4-F-Ph, C⁴—/C⁵—/C⁶—H 2-MeS(O)-Ph), 7.95 (d, 1 H, 7.2 Hz, C³—H2-MeS(O)-Ph), 7.99-8.03 (m, 2H, 4-Pyr), 8.55-8.58 (m, 2H, 4-Pyr)

4-[5-(4-Fluorophenyl)-2-(3-methylsulfanylbenzylsulfanyl)-1H-imidazol-4-yl]-pyridine(17l)

Using the general method A, the title compound was obtained from 1a (1.1g; 4.1 mmol) and 1-chloromethyl-3-methylsulfanylbenzene (0.7 g; 4.1mmol) after a reaction time of 11 hours and recrystallization from EtOH.M.p. 218° C.

IR (KBr): 1225 cm⁻¹ (C—F)

¹H-NMR (DMSO-d₆): δ (ppm) 2.40 (s, 3H, CH₃), 4.46 (s, 2H, CH₂),7.16-7.43 (m, 6H, 4-F-Ph and 3-MeS-Ph), 7.56-7.63 (m, 2H, 4-F-Ph),7.90-7.93 (m, 2H, 4-Pyr), 8.66-8.69 (m, 2H, 4-Pyr), NH not visible

4-[5-(4-Fluorophenyl)-2-(3-methanesulfinylbenzylsulfanyl)-1H-imidazol-4-yl]-pyridine(17m)

A 35% strength solution of H₂O₂ (0.13 ml; 1.3 mmol) was added dropwiseto a suspension of 17 l (0.50 g; 1.2 mmol) in glacial acetic acid (7ml). The reaction mixture was stirred at room temperature for 20.5 h,diluted with H₂O (5 ml), adjusted to pH 9 using 25% strength ammoniawater and extracted with ethyl acetate (3×). The combined organicextract was washed with saturated NaCl solution (3×) and dried overNa₂SO₄. The oily crude product obtained after removal of the solvent wastriturated with diethyl ether/ethyl acetate (1+1) and the semi-solidresidue was purified by column chromatography (RP-18, MeOH). M.p. 171°C.

IR (KBr): 1228 (C—F), 1019 cm⁻¹ (S═O)

¹H-NMR (CD₃OD): δ (ppm) 2.67 (s, 3H, CH₃), 4.37 (s, 2H, CH₂), 7.13-7.21(m, 2H, 4-F-Ph), 7.37-7.58 (m, 8H, 4-Pyr, 4-F-Ph and 3-MeS(O)-Ph),8.40-8.43 (m, 2H, 4-Pyr)

EXAMPLE 18

2-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]phenol(18a)

Using the general method B (23 h, room temperature), the title compoundwas obtained from 1a (0.20 g; 0.7 mmol) and 2-hydroxymethylphenol (0.10g; 0.8 mmol) after trituration with EtOH. M.p. 200° C. (decomposition)

IR (ATR): 1266 (OH bending), 1222 (C—F), 1005 (C—O)

¹H-NMR (DMSO-d₆): δ (ppm) 4.37 (s, 2H, CH₂), 6.70-6.85 (m, 2H, 2-HO-Ph),7.05-7.14 (m, 1H, 2-HO-Ph), 7.23-7.53 (m, 7H, 4-Pyr, 4-F-Ph and2-HO-Ph), 8.46-8.49 (m, 2H, 4-Pyr), 9.95 (bs, 1 H, exchangeable, OH),12.81 (bs, 1H, exchangeable, NH)

3-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]phenyl(18b)

Using the general method B (9 h, reflux), the title compound wasobtained from 1a (0.20 g; 0.7 mmol) and 3-hydroxymethylphenol (0.10 g;0.8 mmol) after purification by column chromatography (SiO₂ 60,CH₂Cl₂/EtOH 9+1).

M.p. 230° C.

IR (ATR): 1287 (OH bending), 1241 (C—F), 1007 cm⁻¹ (C—O)

¹H-NMR (DMSO-d₆): δ (ppm) 4.34 (s, 2H, CH₂), 6.65 (dd, 1H, 1.4/8.0 Hz,3-HO-Ph C⁴—H), 6.79-6.82 (m, 2H, 3-HO-Ph C²—/C⁶—H), 7.07-7.15 (m, 1H,3-HO-Ph C⁵—H), 7.27-7.53 (m, 6H, 4-Pyr and 4-F-Ph), 9.45 (s, 1H,exchangeable, OH), 12.83 (bs, 1H, exchangeable, NH)

4-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]phenol(18c)

Using the general method B (14 h, room temperature), the title compoundwas obtained from 1a (0.20 g; 0.7 mmol) and 4-hydroxymethylphenol (0.10g; 0.8 mmol) after purification by column chromatography (SiO₂ 60,CH₂Cl₂/EtOH 9+1).

M.p. 250° C. (decomposition)

IR (ATR): 1271 (OH bending), 1232 (C—F), 1004 cm⁻¹ (C—O)

¹H-NMR (DMSO-d₆): δ (ppm) 4.32 (s, 2H, CH₂), 6.69 (d, 2H, 7.5 Hz,4-HO-Ph), 7.19 (d, 2H, 7.9 Hz, 4-HO-Ph), 7.27-7.51 (m, 6H, 4-Pyr and4-F-Ph), 8.43-8.53 (m, 2H, 4-Pyr), 9.41 (s, 1H, exchangeable, OH), 12.79(bs, 1H, exchangeable, NH)

2-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-4-methylsulfanylphenol(18d)

Using the general method B (1 h, room temperature), the title compoundwas obtained from 1a (0.50 g; 2.9 mmol) and 8a (0.50 g; 2.9 mmol) aftertrituration with MeOH. M.p. 243° C.

IR (KBr): 1275 (OH bending), 1230 (C—F), 1005 cm⁻¹ (C—O)

¹H-NMR (DMF-d₇): δ (ppm) 2.36 (s, 3H, CH₃), 4.46 (s, 2H, CH₂), 6.90 (d,1H, 8.4 Hz, 2-HO-Ph C³—H), 7.13 (dd, 1H, 2.3/8.3 Hz, 2-HO-Ph C⁴—H),7.27-7.35 (m, 3H, 4-F-Ph and 2-HO-Ph C⁶—H), 7.51-7.53 (m, 2H, 4-Pyr),7.58-7.65 (m, 2H, 4-F-Ph), 8.52-8.55 (m, 2H, 4-Pyr), 10.30-10.70 (bs,1H, exchangeable, NH), OH not visible

4-Chloro-2-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-6-methylsulfanylphenol(18e)

Using the general method B (1.5 h, 75° C.), the title compound wasobtained from 1a (0.80 g; 3.0 mmol) and 8b (0.60 g; 3.0 mmol) aftertrituration with MeOH. M.p. 220° C. (decomposition)

IR (KBr): 1259 (OH bending), 1225 (C—F), 1007 cm⁻¹ (C—O)

¹H-NMR (DMSO-d₆): δ (ppm) 2.34 (s, 3H, CH₃), 4.38 (s, 2H, CH₂), 6.97 (d,1H, 2.3 Hz, 3-Cl-Ph C²—H), 7.17 (d, 1H, 2.3 Hz, 3-Cl-Ph C⁴—H), 7.23-7.51(m, 6H, 4-Pyr and 4-F-Ph), 8.48-8.50 (m, 2H, 4-Pyr), 12.74 (bs, 1H,exchangeable, NH), OH not visible

4-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-2-methylsulfanylphenol(18f)

Using the general method B (2 h, room temperature), the title compoundwas obtained from 1a (0.20 g; 0.7 mmol) and 8c (0.14 g, 0.8 mmol) aftertrituration with MeOH. M.p. 230° C. (decomposition)

IR (KBr): 1227 (C—F), 1019 cm⁻¹ (C—O)

¹H-NMR (CD₃OD): δ (ppm) 2.21 (s, 3H, CH₃), 4.17 (s, 2H, CH₂), 6.69 (d,1H, 8.0 Hz, 4-HO-Ph C³—H), 6.90-7.01 (m, 2H, 4-HO-Ph C²—/C⁶—H),7.12-7.21 (m, 2H, 4-F-Ph), 7.32-7.53 (m, 4H, 4-Pyr and 4-F-Ph),8.39-8.43 (m, 2H, 4-Pyr)

2-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-4-methanesulfinylphenol(18g)

Using the general method B (1 h, room temperature), the title compoundwas obtained from 1a (0.27 g; 1.0 mmol) and 8a (0.17 g; 1.0 mmol) withaddition of 35% strength H₂O₂ solution after recrystallization fromtoluene/THF (1+1). M.p. 216° C.

IR (KBr): 1278 (OH bending), 1232 (C—F), 1031 (S═O), 1003 cm⁻¹ (C—O)

¹H-NMR (CD₃OD): δ (ppm) 2.60 (s, 3H, CH₃), 4.33 (s, 2H, CH₂), 6.96 (d,1H, 8.2 Hz, 2-HO-Ph C³—H), 7.11-7.21 (m, 2H, 4-F-Ph), 7.41-7.47 (m, 6H,4-Pyr, 4-F-Ph and 2-HO-Ph C⁴—/C⁶—H), 8.39-8.42 (m, 2H, 4-Pyr)

4-Chloro-2-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-6-methanesulfinylphenol(18h)

Using the general method B (1.5 h, 75° C.), the title compound wasobtained from 1a (0.27 g; 1.0 mmol) and 8b (0.21 g, 1.0 mmol) withaddition of 35% strength H₂O₂ solution after purification by columnchromatography (SiO₂ 60, acetone). M.p. 175° C. (decomposition)

IR (KBr): 1265 (OH bending), 1236 (C—F), 1051 (S═O), 1005 cm⁻¹ (C—O)

¹H-NMR (CD₃OD): δ (ppm) 2.72 (s, 3H, CH₃), 4.39 (s, 2H, CH₂), 7.14-7.23(m, 2H, 4-F-Ph), 7.39 (d, 1H, 2.6 Hz, 3-Cl-Ph C²—H), 7.42-7.49 (m, 6H,4-Pyr, 4-F-Ph and 3-Cl-Ph C⁴—H), 8.43-8.46 (m, 2H, 4-Pyr)

EXAMPLE 19

4-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-2-methanesulfinylphenol(19)

Using the general method B (2.5 h, room temperature), the title compoundwas obtained from 1a (0.20 g; 0.7 mmol) and 8c (0.14 g; 0.8 mmol) withaddition of 35% strength H₂O₂ solution after trituration with acetone.

M.p. 185° C. (decomposition)

IR (KBr): 1296 (OH bending), 1230 (C—F), 1062 (S═O), 1013 cm⁻¹ (C—O)

¹H-NMR (CD₃OD): δ (ppm) 2.70 (s, 3H, CH₃), 4.28 (s, 2H, CH₂), 6.78 (d,1H, 8.3 Hz, 4-HO-Ph C³—H), 7.12-7.21 (m, 2H, 4-F-Ph), 7.28 (dd, 1H,2.2/8.3 Hz, 4-HO-Ph C²—H), 7.39-7.46 (m, 5H, 4-Pyr, 4-F-Ph and 4-HO-PhC⁶-H), 8.40 (m, 2H, 4-Pyr)

EXAMPLE 20

4-Fluoro-N-methoxy-N-methylbenzamide (20)

A suspension of 4-fluorobenzoic acid (20 g, 143 mmol) in thionylchloride (130 g; 1.1 mol) was stirred under reflux for 6 h: vigorousevolution of gas, clear solution after about 10 min, deepening of thecolor from yellow to orange. Excess thionyl chloride was removed bydistillation (initially atmospheric pressure/40° C., then membrane pumpvacuum/400° C.). From the distillation residue, 4-fluorobenzoyl chloridewas distilled off under membrane pump vacuum at 90° C. over a shortcolumn. The reaction product crystallized on storing in a fridge (n²⁰D1.5315; m.p. 9° C., yield 20 g/89%). Freshly distilled triethylamine (29ml) was added to a suspension of N,O-dimethylhydroxylamine hydrochloride(9.0 g; 92 mmol) in CH₂Cl₂ (75 ml). The reaction mixture was stirred atroom temperature for 2 h and then cooled to −10° C. With cooling,4-fluorobenzoyl chloride (13.5 g; 85 mmol) was, over a period of 6 min,added dropwise to the initial charge. After the addition had ended,cooling was removed and the reaction mixture was stirred at roomtemperature for 1.5 h. The light-brown suspension was poured into H₂O(100 ml). The organic phase was removed and the aqueous phase wasextracted with diethyl ether (2×). The combined extract was washed withsaturated NaCl solution, dried over Na₂SO₄ and concentrated. The oilybrown residue crystallized on cooling and scratching. The crude productwas dried using an oil pump (residual triethylamine!) and reactedwithout further purification.

¹H-NMR (CDCl₃): δ (ppm) 3.37 (s, 3H, NCH₃), 3.54 (s, 3H, OCH₃),7.04-7.13 (m, 2H, 4-F-Ph), 7.71-7.78 (m, 2H, 4-F-Ph)

EXAMPLE 21

2-(2-Chloropyridin-4-yl)-1-(4-fluorophenyl)ethanone (21a)

n-BuLi (15% strength solution in n-hexane, 45 ml, 104 mmol) was addeddropwise to a solution, cooled to −85° C., of diisopropylamine (15 ml,106 mmol) in abs. THF (150 ml) in a double-necked flask which had beendried by heating and flushed with argon: temperature increase to −50° C.After the addition had ended, the light-yellow solution was stirred at−85° C for 55 min. At −85° C., a solution of 2-chloro-4-methylpyridine(2-chloro-γ-picoline, 8.6 g; 68 mmol) in abs. THF (75 ml) was addeddropwise to this initial charge: temperature increase to −50° C.,initial change of color to purple. After the addition had ended, thereaction mixture was stirred at −85° C. for 1 h, and a solution of 20(12.4 g; 68 mmol) in abs. THF (75 ml) was added at this temperature overa period of 3 min: temperature increase to −60° C. The purple slurry ofthe reaction mixture was stirred at −85° C. for 1 h and then, over aperiod of 1 h, warmed to 0° C. The mixture was poured into saturatedNaCl solution (300 ml) which had been covered with ethyl acetate (300ml). The organic phase was removed and the aqueous phase was extractedwith ethyl acetate (2×250 ml) and a little brown foamy precipitate of1,3-bis-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)propan-2-ol separatedoff at the interface. The combined organic extract was washed withsaturated NaCl solution, dried over NaSO₄ and concentrated. The oilyresidue was taken up in a little tert-butyl methyl ether and stored at4° C. overnight. The crystals were filtered off and dried.

¹H-NMR (CDCl₃): δ (ppm) 4.26 (s, 2H, CH₂), 7.11-7.26 (m, 4H, C³—/C⁵—H2-Cl-Pyr and 4-F-Ph), 7.99-8.06 (m, 2H, 4-F-Ph), 8.35 (dd, 1H, 0.6/5.1Hz, C⁶—H 2-Cl-Pyr)

1-(4-Fluorophenyl)-2-(2-fluoropyridin-4-yl)ethanone (21b)

21b was prepared from 2-fluoro-4-methylpyridine (13.9 g; 125 mmol) usingthe method described in the synthesis of 21a.

¹H-NMR (CDCl₃): δ (ppm) 4.32 (s, 2H, CH₂), 6.85-6.86 (m, 1H, C³—H2-F-Pyr), 7.08-7.19 (m, 3H, C⁵—H 2-F-Pyr and 4-F-Ph), 8.00-8.07 (m, 2H,4-F-Ph), 8.18 (d, 1H, 5.1 Hz, C⁶—H 2-F-Pyr)

2-(2-Bromopyridin-4-yl)-1-(4-fluorophenyl)ethanone (21c)

21c was prepared from 2-bromo-4-methylpyridine (9.6 g; 56 mmol) usingthe method described in the synthesis of 21a.

¹H-NMR (CDCl₃): δ (ppm) 4.35 (s, 2H, CH₂), 7.17-7.37 (m, 3H, 2-Br-Pyrand 4-F-Ph) 7.50 (s, 1H, C³—H 2-Br-Pyr), 8.07-8.15 (m, 2H, 4-F-Ph), 8.42(d, 1H, 5.1 Hz, C⁶—H 2-Br-Pyr)

EXAMPLE 22

1-(2-Chloropyridin-4-yl)-2-(4-fluorophenyl)ethane-1,2-dione-1-oxime(22a)

With stirring and cooling in a water bath (about 10° C.), a solution ofNaNO₂ (0.85 g; 12.3 mmol) in H₂O (10 ml) was added dropwise over aperiod of 2.5 min to a solution of 21a (3.0 g; 12 mmol) in glacialacetic acid. After the addition had ended, the reaction mixture wasstirred at room temperature for 0.5 h, H₂O (60 ml) was added andstirring at room temperature was continued for 3 h. The light-beigeprecipitate was filtered off, washed with water and dried under reducedpressure over CaCl₂.

¹H-NMR (DMSO-d₆): δ (ppm) 7.34-7.52 (m, 4H, C³—/C⁵—H 2-Cl-Pyr and4-F-Ph), 7.93-8.00 (m, 2H, 4-F-Ph), 8.47 (d, 1H, 5.2 Hz, C⁶—H 2-Cl-Pyr),12.71 (bs, 1H, exchangeable, OH)

1-(2-Fluoropyridin-4-yl)-2-(4-fluorophenyl)ethane-1,2-dione-1-oxime(22b)

22b was prepared from 21b (10.0 g; 43 mmol) using the method describedin the synthesis of 22a.

¹H-NMR (DMSO-d₆): δ (ppm) 7.19-7.20 (m, 1H, C³—H 2-F-Pyr), 7.35-7.47 (m,3H, C⁵—H 2-F-Pyr and 4-F-Ph), 7.91-7.98 (m, 2H, 4-F-Ph), 8.29 (d, 1H,5.3 Hz, C⁶—H 2-F-Pyr), 12.69 (s, 1H, exchangeable, OH)

1-(4-Fluorophenyl)-2-(2-isopropoxypyridin-4-yl)ethane-1,2-dione-2-oxime(22c)

A solution of 22b (200 mg; 0.76 mmol) in HCl-saturated isopropanol (15ml) was stirred under reflux for 2.5 h. The solution was concentratedand the yellowish-white residue was triturated with a little ethanol,filtered off and dried.

¹H-NMR (DMSO-d₆): δ (ppm) 1.24 (d, 6H, 6.2 Hz, 2×CH₃), 5.15-5.27 (m, 1H,Me-thin-H), 6.54 (s, 1H, C³—H 2-iso-O-Pyr), 7.08 (dd, 1H, 1.2/5.3 Hz,C⁵—H 2-iso-O-Pyr), 7.36-7.49 (m, 2H, 4-F-Ph), 7.88-7.97 (m, 2H, 4-F-Ph),8.19 (d, 1H, 5.4 Hz, C⁶—H 2-iso-O-Pyr), 12.44 (bs, 1H, exchangeable, OH)

1-(2-Bromopyridin-4-yl)-2-(4-fluorophenyl)ethane-1,2-dione-1-oxime (22d)

22d was prepared from 21c (5.0 g; 17 mmol) using the method described inthe synthesis of 22a.

¹H-NMR (DMSO-d₆): δ (ppm) 7.40-7.48 (m, 3H, C³—H 2-Br-Pyr and 4-F-Ph),7.65 (d, 1H, 0.8 Hz, C⁵—H 2-Br-Pyr), 7.93-8.01 (m, 2H, 4-F-Ph), 8.45 (d,1H, 5.2 Hz, C⁶—H 2-Br-Pyr), 12.72 (bs, 1H, exchangeable, OH)

EXAMPLE 23

2-Amino-2-(2-chloropyridin-4-yl)-1-(4-fluorophenyl)ethanonehydrochloride (23a)

With gentle heating, 22a (1.5 g; 5.4 mmol) was dissolved in methanol (15ml). The solution was cooled to room temperature, HCl-containingmethanol (20 ml) was added and the mixture was transferred into atwo-necked flask. Pd—C 10% (150 mg) was introduced into the initialcharge. The reaction vessel was evacuated using an oil pump, and H₂ wasthen introduced via a gas inlet capillary (4×). At room temperature, thesuspension was shaken in a closed three-necked flask under an atmosphereof H₂ (240 strokes/min) until no more starting material could bedetected by thin-layer chromatography (6 h). The suspension was filteredand the catalyst was washed with plenty of methanol. The combinedfiltrate was concentrated and the mustard-colored solid-amorphousresidue was dried using an oil pump. The crude product was used withoutfurther purification for the next reaction step.

¹H-NMR (DMSO-d₆): δ (ppm) 6.53 (bs, 1H, methyne-H), 7.35-7.45 (m, 2H,4-F-Ph), 7.59 (dd, 1H, 1.5/5.2 Hz, C⁵—H 2-Cl-Pyr), 7.85 (d, 1H, 0.9Hz,C³—H 2-Cl-Pyr), 8.17-8.25 (m, 2H, 4-F-Ph), 8.49 (d, 1H, 4.9 Hz, C⁶—H2-Cl-Pyr), 9.33 (bs, 3H, exchangeable, NH₃ ⁺)

2-Amino-2-(2-fluoropyridin-4-yl)-1-(4-fluorophenyl)ethanonehydrochloride (23b)

With gentle heating, 22b (5.0 g; 19 mmol) was dissolved inHCl-containing isopropanol (IsOH/HCl-saturated IsOH 1+1, 60 ml). Theyellowish solution was cooled to room temperature and transferred into atwo-necked flask (100 ml). Pd—C 10% (1.5 g) was introduced into theinitial charge. The reaction vessel was evacuated using an oil pump andH₂ was then introduced via a gas inlet capillary (4×). At roomtemperature, the suspension was shaken in a closed three-necked flaskunder an atmosphere of H₂ (240 strokes/min) until no more startingmaterial could be detected by thin-layer chromatography (6.5 h). Thecatalyst was filtered off. The filtration residue was washed with plentyof methanol (about 800 ml). The combined filtrates were concentrated andthe solid-amorphous residue was dried on an oil pump. The crude productwas used without further purification for the next reaction step.

¹H-NMR (DMSO-d₆): δ (ppm) 6.58 (bs, 1H, methyne-H), 7.33-7.41 (m, 2H,4-F-Ph), 7.54 (m, 2H, C³—/C⁵—H 2-F-Pyr), 8.14-8.25 (m, 2H, 4-F-Ph), 8.30(d, 1H, 5.5 Hz, C⁶—H 2-F-Pyr), 9.40 (bs, 3H, exchangeable, NH₃ ⁺)

2-Amino-1-(4-fluorophenyl)-2-(2-isopropoxypyridin-4-yl)ethanonehydrochloride (23c)

23c was prepared from 22c (2.0 g; 7.6 mmol) using the method describedin the synthesis of 23a.

¹H-NMR (DMSO-d₆): δ (ppm) 1.23 (d, 6H, 5.6 Hz, 2×CH₃), 5.09-5.22 (m, 1H,methyne-H CH(CH₃)₂), 6.38-6.41 (bs, 1H, methyne-H CH—NH₃ ⁺), 7.00-7.08(m, 2H, 2-iso-O-Pyr), 7.33-7.46 (m, 2H, 4-F-Ph), 8.14-8.23 (m, 3H,2-iso-O-Pyr and 4-F-Ph), 9.21 (bs, 3H, exchangeable, NH₃ ⁺)

2-Amino-1-(4-fluorophenyl)-2-(2-methoxypyridin-4-yl)ethanonehydrochloride (23d)

23d was formed by treating 22b (7.5 g; 29 mmol) under the conditionsdescribed in the synthesis of 23a.

¹H-NMR (DMSO-d₆): δ (ppm) 3.83 (s, 3H, CH₃), 6.44 (bs, 1H, methyne-H),7.13-7.16 (m, 2H, C³—/C⁵—H 2-MeO-Pyr), 7.34-7.46 (m, 2H, 4-F-Ph),8.16-8.25 (m, 3H, C⁶—H 2-MeO-Pyr and 4-F-Ph), 9.29 (bs, 3H,exchangeable, NH₃ ⁺)

2-Amino-1-(4-fluorophenyl)-2-pyridin-4-ylethanone hydrochloride (23e)

23e was formed by treating 22c (4.0 g; 12.4 mmol) under the conditionsdescribed in the synthesis of 23b.

¹H-NMR (DMSO-d₆): δ (ppm) 6.78 (bs, 1H, methyne-H), 7.32-7.38 (m, 2H,4-F-Ph), 8.07-8.13 (m, 2H, 4-Pyr), 8.17-8.27 (m, 2H, 4-F-Ph), 8.92-8.95(m, 2H, 4-Pyr), 9.43 (bs, 3H, exchangeable, NH₃ ⁺)

2-Amino-2-(2-bromopyridin-4-yl)-1-(4-fluorophenyl)ethanone hydrochloride(23f)

A solution of 22d (1.8 g; 5.6 mmol) in absolute ethanol (30 ml) wascooled to −10° C., and concentrated sulfuric acid (1.3 ml) was added.With cooling, zinc dust (1.1 g) was added a little at a time to theinitial charge. The reaction mixture was stirred at −10° C. for 30 minand then warmed to room temperature. The gray-green suspension wasfiltered and the white residue (ZnSO₄) was washed with plenty ofethanol. The combined yellow filtrate was concentrated and the solidyellowish residue was dried using an oil pump.

¹H-NMR (DMSO-d₆): δ (ppm) 6.39 (bs, 1H, methyne-H), 7.35-7.44 (m, 2H,4-F-Ph), 7.56 (dd, 1H, 1.4/5.1 Hz, C⁵—H 2-Br-Pyr), 7.91 (s, 1H,C³—H2-Br-Pyr), 8.12-8.19 (m, 2H, 4-F-Ph), 8.46 (d, 1H, 5.1 Hz,C⁶—H2-Br-Pyr), 8.94 (bs, 3H, exchangeable, NH₃ ⁺)

EXAMPLE 24

4-(2-Chloropyridin-4-yl)-5-(4-fluorophenyl)-1,3-dihydroimidazole-2-thione(24a)

With gentle heating, 23a (2.9 g; about 9.6 mmol) was dissolved inabsolute DMF (75 ml). Potassium thiocyanate (1.9 g; 19.6 mmol) wasintroduced into the clear orange-red solution: immediate opalescence anda lighter color. The reaction mixture was stirred under reflux for 1.5h. The suspension was cooled to room temperature and, with H₂O cooling,diluted dropwise with H₂O (about 140 ml). The yellow precipitate wasfiltered off, washed with H₂O and dried under reduced pressure overCaCl₂.

¹H-NMR (DMSO-d₆): δ (ppm) 7.12-7.52 (m, 6H, C³—/C⁵—H 2-Cl-Pyr and4-F-Ph), 8.27 (d, 1H, 5.2 Hz, C⁶—H 2-Cl-Pyr), 12.82 (bs, 2H,exchangeable, 2×NH)

4-(4-Fluorophenyl)-5-(2-fluoropyridin-4-yl)-1,3-dihydroimidazole-2-thione(24b)

24b was prepared from 23b (6.1 g; 20 mmol) using the method described inthe synthesis of 24a.

¹H-NMR (DMSO-d₆): δ (ppm) 7.12-7.16 (m, 2H, C³—/C⁵—H 2-F-Pyr), 7.28-7.27(m, 2H, 4-F-Ph), 7.46-7.55 (m, 2H, 4-F-Ph), 8.13 (d, 1H, 5.1 Hz, C⁶—H2-F-Pyr), 12.85 (bs, 2H, exchangeable, 2×NH)

4-(4-Fluorophenyl)-5-(2-isopropoxypyridin-4-yl)-1,3-dihydroimidazole-2-thione(24c)

24c was prepared from 23c (2.5 g; 7.6 mmol) using the method describedin the synthesis of 24a.

¹H-NMR (DMSO-d₆): δ (ppm) 1.24 (d, 6H, 6.2 Hz, 2×CH₃), 5.10-5.19 (m, 1H,methyne-H), 6.69-6.76 (m, 2H, 2-iso-O-Pyr), 7.24-7.32 (m, 2H, 4-F-Ph),7.42-7.49 (m, 2H, 4-F-Ph), 8.02 (d, 1H, 5.5 Hz, C⁶—H 2-iso-O-Pyr), 12.68(bs, 2H, exchangeable, 2×NH)

4-(4-Fluorophenyl)-5-(2-methoxypyridin-4-yl)-1,3-dihydroimidazole-2-thione(24d)

Potassium thiocyanate (2 g, 20.6 mmol) was introduced into a solution of23d (3.2 g; 10.8 mmol) in 10% strength hydrochloric acid (50 ml). Thereaction mixture was stirred under reflux for 30 min. The orangesolution was cooled and neutralized using 10% strength NaHCO₃ solution.The precipitate was filtered off, washed with H₂O and dried underreduced pressure over CaCl₂. The crude product was triturated withethanol, and insoluble components were filtered off. On standing, 24dprecipitated from the ethanolic filtrate.

¹H-NMR (DMSO-d₆): δ (ppm) 3.81 (s, 3H, OCH₃), 6.79-6.82 (m, 2H,C³—/C⁵—H2-MeO-Pyr), 7.26-7.50 (m, 4H, 4-F-Ph), 8.06 (d, 1H, 5.3 Hz, C⁶—H2-MeO-Pyr), 12.65 (bs, 2H, exchangeable, 2×NH)

EXAMPLE 25

2-Chloro-4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine(25a)

Using the general method A, the title compound was obtained from 24a(0.5 g; 1.6 mmol) and methyl iodide (0.35 g; 2.5 mmol) after a reactiontime of 12 hours and purification by column chromatography (Al₂O₃,CH₂Cl₂/ethyl acetate 1+1). M.p. 236° C.

IR (ATR): 3126, 3057, 2929, 1591, 1529, 1499, 1389, 1231 (C—F), 1159,996, 976, 844, 780 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 2.62 (s, 1H, CH₃), 7.27-7.36 (m, 3H, 2-Cl-Pyrand 4-F-Ph), 7.45-7.55 (m, 3H, 2-Cl-Pyr and 4-F-Ph), 8.24 (d, 1H, 5.1Hz, C⁶—H 2-Cl-Pyr), 12.85 (bs, 1H, exchangeable, NH)

2-Fluoro-4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine(25b)

Using the general method A, the title compound was obtained from 24b(0.95 g; 3.3 mmol) and methyl iodide (1.4 g; 9.9 mmol) after a reactiontime of 40 hours. The crude product was boiled with CH₂Cl₂/ethyl acetate(1+1). The combined organic extract was decolorized using Al₂O₃, and theresidue obtained after concentration of the filtrate was triturated witha little EtOH. M.p. 224° C.

IR (ATR): 3073, 1609, 1497, 1421, 1234, 1219 (C—F), 1159, 1002, 883,851, 833, 815 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 2.62 (s, 3H, CH₃), 7.08 (s, 1H, C³—H 2-F-Pyr),7.26-7.35 (m, 3H, C⁵—H 2-F-Pyr and 4-F-Ph), 7.46-7.54 (m, 2H, 4-F-Ph),8.08 (d, 1H, 5.3 Hz, C⁶—H 2-F-Pyr), 12.85 (bs, 1H, exchangeable, NH)

4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-2-isopropoxypyridin(25c)

NaH (55-65%; 1.0 g; about 23 mmol) was introduced into a solution of 24c(4.0 g; 13.8 mmol) in absolute THF (60 ml). This initial charge wasstirred at room temperature for 5 min, and a solution of methyl iodide(2.2 g; 17.3 mmol) in absolute THF (5 ml) was added dropwise with H₂Ocooling. The reaction mixture was stirred at room temperature for 1 h.The clear brown solution was concentrated and the residue was taken upin H₂O. The aqueous solution was neutralized using 10% strengthhydrochloric acid and extracted with ethyl acetate (2×). The combinedorganic extract was washed with saturated NaCl solution, dried overNa₂SO₄ and concentrated. The semi-solid residue was extracted by boilingwith tert-butyl methyl ether (2×) and filtered. The clear etherealfiltrate was concentrated and the solid residue was triturated with alittle tert-butyl methyl ether, filtered off and dried. Further reactionproduct was obtained by column chromatographic separation of the motherliquor (SiO₂ 60, CH₂Cl₂/ethyl acetate 1+1). M.p. 141° C.

IR (ATR): 2928, 1610, 1544, 1509, 1412, 1314, 1222 (C—F), 1104, 1005,954, 865, 843, 816 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 1.28 (d, 6H, 6.1 Hz, 2×CH₃), 2.63 (s, 3H, SCH₃),5.08-5.14 (m, 1H, methyne-H), 6.76 (s, 1H, C³—H 2-iso-O-Pyr), 6.88 (dd,1H, 1.4/5.4 Hz, C⁵—H 2-iso-O-Pyr), 7.10-7.19 (m, 2H, 4-F-Ph), 7.40-7.47(m, 2H, 4-F-Ph), 7.95 (dd, 1H, 0.7/5.4 Hz, C⁶—H 2-iso-O-Pyr)

4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-2-methoxypyridine(25d)

A solution of 24d (1.0 g; 3.3 mmol) and methyl iodide (5.6 g; 39 mmol)in methanol (50 ml) was stirred under reflux for 3 h. The reactionmixture was cooled and filtered. The filtrate was concentrated and theresidue was taken up in ethanol. Insoluble components were filtered offand the filtrate was concentrated. The residue was taken up inCH₂Cl₂/EtOH (9+1). Insoluble components were filtered off, and thefiltrate was separated by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH9+1). M.p. 158° C.

IR (ATR): 1618, 1608, 1497, 1391, 1222 (C—F), 1212, 1036, 835, 825 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 2.67 (s, 3H, SCH₃), 3.90 (s, 3H, OCH₃),6.87-6.89 (m, 1H, C³—H 2-MeO-Pyr), 6.98 (dd, 1H, 1.5/5.5 Hz,C⁵-H2-MeO-Pyr), 7.16-7.24 (m, 2H, 4-F-Ph), 7.46-7.53 (m, 2H, 4-F-Ph),8.03 (dd, 1H, 0.7/5.5 Hz, C⁶—H 2-MeO-Pyr)

4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-1H-pyridin-2-one(25e)

When 23d (8.8 g; 31 mmol) was treated with potassium thiocyanate inboiling DMF analogously to the method described for 24a, the onlyreaction product obtained was 25e. M.p. 314° C. (decomposition). Aftercyclization, giving the 1,3-dihydroimidazolethione, the methyl groupfrom the methoxy substituent is transferred to the nucleophilic sulfuratom of the thione, with formation firstly of the2-methylsulfanyl-3H-imidazole and, secondly, the2-hydroxypyridine/1H-pyridin-2-one.

IR (ATR): 1634 (pyridone I), 1610, 1557 (pyridone II), 1493, 1220 (C—F),968, 837, 800 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 2.61 (s, 3H, SCH₃), 6.16 (bs, 1H, C³—Hpyridone), 6.34 (s, 1H, C⁵—H pyridone), 7.25-7.33 (m, 3H, C⁶—H pyridoneand 4-F-Ph), 7.46-7.53 (m, 2H, 4-F-Ph), 11.38 (bs, 1H, exchangeable,pyridone-NH), 12.71 (bs, 1H, exchangeable, imidazole-NH)

Benzyl{4-[S-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-amine(25f)

Using the general method C, the title compound was obtained from 25b(0.2 g; 0.7 mmol) and benzylamine (0.8 g; 7.5 mmol) after a reactiontime of 5 hours at 160° C. and separation by column chromatography(Al₂O₃, CH₂Cl₂/ethyl acetate 1+1).

M.p. 152° C. (decomposition)

IR (ATR): 3234 (NH), 3006, 2916, 1601, 1583, 1501, 1451, 1432, 1353,1225 (C—F), 1074, 844, 813, 729, 695 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 2.59 (s, 3H, CH₃), 4.37 (s, 2H, CH₂), 6.56-6.59(m, 2H, C³—/C⁵—H 2-amino-Pyr), 7.04-7.44 (m, 9H, Ph and 4-F-Ph), 7.83(d, 1H, 5.6 Hz, C⁶—H 2-amino-Pyr)

{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-(4-methoxybenzyl)amine(25g)

Using the general method C, the title compound was obtained from 25b(0.44 g; 1.5 mmol) and 4-methoxybenzylamine (2.0 g; 14.6 mmol) after areaction time of 7 hours at 160° C. and separation by columnchromatography (SiO₂, CH₂Cl₂/EtOH 9+1).

M.p. 207° C.

IR (ATR): 1598, 1558,1510, 1244, 1217 (C—F), 846, 812 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 2.61 (s, 3H, SCH₃), 3.75 (s, 3H, OCH₃), 4.30 (s,2H, CH₂), 6.56-6.59 (m, 2H, C³—/C⁵—H 2-amino-Pyr), 6.81-7.30 (m, 6H,4-MeO-Ph and 4-F-Ph), 7.39-7.46 (m, 2H, 4-F-Ph), 7.84 (d, 1H, 6.0 Hz,C⁶—H 2-amino-Pyr)

{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-(4-methylbenzyl)amine(25h)

Using the general method C, the title compound was obtained from 25b(0.2 g; 0.7 mmol) and 4-methylbenzylamine (0.85 g; 7.0 mmol) after areaction time of 6 hours at 160° C. and separation by columnchromatography (SiO₂ 60, CH₂Cl₂/EtOH 9+1). M.p.185° C.

IR (ATR): 1600, 1559, 1502, 1427, 1218 (C—F), 844, 809 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 2.29 (s, 3H, CH3), 2.60 (s, 3H, SCH3), 4.32 (s,2H, CH2), 6.57-6.60 (m, 2H, C3-/C5-H 2-amino-Pyr), 7.05-7.50 (m, 8H,4-Me-Ph and 4-F-Ph), 7.83 (d, 1H, 5.3 Hz, C6-H2-amino-Pyr)

(4-Chlorobenzyl)-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}amine(25i)

Using the general method C, the title compound was obtained from 25b(0.2 g; 0.7 mmol) and 4-chlorobenzylamine (1.0 g; 7.0 mmol) after areaction time of 5.5 hours under reflux and separation by columnchromatography (SiO₂ 60, CH₂Cl₂/EtOH 9+1). M.p. 195° C.

IR (ATR): 3409, 1597, 1549, 1502, 1489, 1422, 1218 (C—F), 843, 814, 793cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 2.60 (s, 3H, SCH₃), 4.38 (s, 2H, CH₂), 6.57-6.60(m, 2H, C³—/C⁵—H 2-amino-Pyr), 7.05-7.14 (m, 2H, 4-F-Ph), 7.22-7.30 (m,4H, 4-Cl-Ph), 7.38-7.45 (m, 2H, 4-F-Ph), 7.83 (d, 1H, 5.7 Hz, C⁶—H2-amino-Pyr)

(3,4-Dichlorobenzyl)-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol4-yl]-pyridin-2-yl}amine(25j)

Using the general method C, the title compound was obtained from 25b(0.2 g; 0.7 mmol) and 3,4-dichlorobenzylamine (1.2 g; 6.8 mmol) after areaction time of 7.5 hours at 160° C. and separation by columnchromatography (SiO₂ 60, CH₂Cl₂/EtOH 9+1). M.p. 212° C.

IR (ATR): 3409, 1600, 1552, 1509, 1490, 1424, 1225 (C—F), 842, 827, 813cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 2.60 (s, 3H, SCH₃), 4.39 (s, 2H, CH₂), 6.56-6.62(m, 2H, C³—/C⁵—H 2-amino-Pyr), 7.06-7.50 (m, 7H, 3,4-di-Cl-Ph and4-F-Ph), 7.84 (d, 1H, 5.5 Hz, C⁶—H 2-amino-Pyr)

{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-phenylamine(25k)

Using the general method C, the title compound was prepared from 25b(0.2 g; 0.7 mmol) and aniline (0.65 g; 7.0 mmol) after a reaction timeof 6 hours under reflux and separation by column chromatography (SiO₂60, CH₂Cl₂/EtOH 9+1). M.p. 228° C.

IR (ATR): 3031, 1610, 1590, 1561, 1504, 1433, 1265, 1225 (C—F), 839,827, 749, 695 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 2.62 (s, 3H, CH₃), 5.95-6.13 (m, 2H,C³—/C⁵—H2-Pyr), 6.68-7.60 (m, 9H, Ph and 4-F-Ph), 7.97-8.01 (m, 1H, C⁶—H2-Amino-Pyr), 8.99 (bs, 1H, exchangeable, anilino-NH), 12.68 (bs, 1H,exchangeable, imidazole-NH)

{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol4-yl]pyridin-2-yl}-phenethylamine(25l)

Using the general method C, the title compound was obtained from 25b(0.2 g; 0.7 mmol) and 2-phenylethylamine (0.85 g; 7.0 mmol) after areaction time of 5.5 hours at 160° C. and separation by columnchromatography (SiO₂ 60, CH₂Cl₂/EtOH 9+1). M.p. 99° C.

IR (ATR): 3409, 1604, 1546, 1504, 1220 (C—F), 838, 813, 698 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 2.61 (s, 3H, SCH₃), 2.81 (t, 2H, 7.7 Hz, NCH₂),3.41 (t, 2H, 7.7 Hz, CH₂Ph), 6.55-6.57 (m, 2H, C³—/C⁵—H 2-amino-Pyr),7.08-7.26 (m, 7H, Ph and 4-F-Ph), 7.42-7.49 (m, 2H, 4-F-Ph), 7.82 (d,1H, 6.1 Hz, C⁶—H 2-amino-Pyr)

(RS)-{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-(1-phenylethyl)amine(25m)

Using the general method C, the title compound was obtained from 25b(0.2 g; 0.7 mmol) and (RS)-1-phenylethylamine (0.80 g; 6.6 mmol) after areaction time of 7 hours at 160° C. and separation by columnchromatography (SiO₂ 60, CH₂Cl₂/EtOH 9+1). M.p. 117-119° C.

IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (C—F), 1157, 838, 814, 699cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 1.37 (d, 3H, 5.5 Hz, CH₃), 2.58 (s, 3H, SCH₃),4.82-5.03 (m, 1H, methyne-H), 6.39-7.74 (m, 12H, Ph, 2-amino-Pyr and4-F-Ph), 12.57 (bs, 1H, exchangeable, NH)

(R)-{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-(1-phenylethyl)amine(25n)

Using the general method C, the title compound was obtained from 25b(0.2 g; 0.7 mmol) and (R)-1-phenylethylamine (0.80 g; 6.6 mmol) after areaction time of 7 hours at 170° C. and separation by columnchromatography (SiO₂ 60, CH₂Cl₂/ethyl acetate 1+1). M.p. 117-119° C.

IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (C—F), 1157, 838, 814, 699cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 1.44 (d, 3H, 6.9 Hz, CH₃), 2.59 (s, 3H, SCH₃),4.62-4.69 (m, 1H, methyne-H), 6.47-6.57 (m, 2H, C³—/C⁵—H2-amino-Pyr),7.05-7.42 (m, 9H, Ph and 4-F-Ph), 7.80 (d, 1 H, 5.5 Hz, C⁶—H2-amino-Pyr)

(S)-{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-(1-phenylethyl)amine(25o)

Using the general method C, the title compound was obtained from 25b(0.2 g; 0.7 mmol) and (S)-1-phenylethylamine (0.80 g; 6.6 mmol) after areaction time of 13 hours at 170° C. and separation by columnchromatography (SiO₂ 60, CH₂Cl₂/ethyl acetate 1+1). M.p. 117-119° C.

IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (C—F), 1157, 838, 814, 699cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 1.44 (d, 3H, 6.9 Hz, CH₃), 2.59 (s, 3H, SCH₃),4.62-4.69 (m, 1H, methyne-H), 6.47-6.57 (m, 2H, C³—/C⁵—H2-amino-Pyr),7.05-7.42 (m, 9H, Ph and 4-F-Ph), 7.80 (dd, 1H, 0.5/5.5 Hz, C⁶—H2-amino-Pyr)

Benzyl-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-methylamine(25p)

Using the general method C, the title compound was obtained from 25b(0.2 g; 0.7 mmol) and N-methylbenzylamine (0.85 g; 7.0 mmol) after areaction time of 7 hours at 180° C. and two column-chromatographicseparations (SiO₂ 60, CH₂Cl₂/ethyl acetate 1+1). M.p. 79° C.

IR (ATR): 2924, 1601, 1494, 1407, 1219 (C—F), 837, 810, 730, 696 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 2.60 (s, 3H, SCH₃), 2.97 (s, 3H, NCH₃), 4.64 (s,2H, CH₂) 6.64-6.66 (m, 2H, C³—/C⁵—H 2-amino-Pyr), 7.02-7.45 (m, 9H, Phand 4-F-Ph), 7.96 (d, 1H, 5.0 Hz, C⁶—H 2-amino-Pyr)

The compounds compiled in Table 2 below were obtained using the abovemethod:

TABLE 2 Ex. Method Name Structure 25q C (4-Fluorophenyl)-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine

25r C (4-Chlorophenyl)-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

25s C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-m-tolylamine

25t C (2,4-Difluorophenyl)-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

25u C (2,6-Dichlorophenyl)-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

25v C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-pyridin-2-yl}-(1-phenylpropyl)amine

25w C 3,3-Diphenylpropyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

25x C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-pyridin-2-yl}naphthalen-1-yl- methylamine

25y C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-pyridin-2-yl}naphthalen-2-yl- methylamine

EXAMPLE 26

4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-2-chloropyridine(26a)

Using the general method A, the title compound was obtained from 24a(0.3 g; 1.0 mmol) and benzyl chloride (0.12 g; 1.0 mmol) after areaction time of 6 hours and purification by column chromatography (SiO₂60, CH₂Cl₂/EtOH 9+1). M.p. 223° C.

IR (ATR): 2939, 1591, 1530, 1505, 1233 (C—F), 997, 838, 782, 700 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 4.43 (s, 2H, CH₂), 7.27-7.47 (m, 11H,2-Cl-Pyr, Ph and 4-F-Ph), 8.26 (d, 1H, 5.2 Hz, C⁶—H 2-Cl-Pyr), 12.94(bs, 1H, exchangeable, NH)

4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-2-fluoropyridine(26b)

Using the general method A, the title compound was obtained from 24b(5.1 g; 17.6 mmol) and benzyl bromide (9.2 g; 54 mmol) after a reactiontime of 1.5 hours and separation by column chromatography (Al₂O₃,CH₂Cl_(2/)ethyl acetate 1+1). M.p. 174° C.

IR (ATR): 3028, 2948, 1611, 1496, 1413, 1228 (C—F), 1203, 1003, 879,838, 698 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 4.43 (s, 2H, CH₂), 7.11 (s, 1H, C³—H 2-F-Pyr),7.25-7.51 (m, 10H, C⁵—H 2-F-Pyr, Ph and 4-F-Ph), 8.10 (d, 1H, 5.3 Hz,C⁶—H 2-F-Pyr), 12.93 (bs, 1H, exchangeable, NH)

Benzyl-{4-[2-benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]pyridin-2-yl}-amine(26c)

Using the general method C, the title compound was obtained from 26b(0.2 g; 0.53 mmol) and benzylamine (0.60 g; 5.6 mmol) after a reactiontime of 6 hours at 180° C. and separation by column chromatography (SiO₂60, CH₂Cl₂/ethyl acetate 1+1). M.p. 185° C.

IR (ATR): 3407 (NH), 3025, 2855, 2713, 1599, 1550, 1489, 1356, 1220(C—F), 1155, 840, 814, 693 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 4.21 (s, 2H, NCH₂), 4.38 (s, 2H, SCH₂),6.52-6.55 (m, 2H, C³—/C⁵—H 2-amino-Pyr), 7.03-7.38 (m, 9H, Ph and4-F-Ph), 7.83 (d, 1H, 5.7 Hz, C⁶—H 2-amino-Pyr)

(RS)-{4-[2-Benzylsulfanyl-S-(4-fluorophenyl)-3H-imidazol-4-yl]pyridin-2-yl}-(1-phenylethyl)amine(26d)

Using the general method C, the title compound was obtained from 26b(0.2 g; 0.53 mmol) and (RS)-1-phenylethylamine (0.65 g; 5.4 mmol) aftera reaction time of 15 hours at 150° C. and separation by columnchromatography (SiO₂ 60, CH₂Cl2/ethyl acetate 1+1). M.p. 145° C.

IR (ATR): 3028, 1606, 1546, 1494, 1450, 1221 (C—F), 1157, 837, 813, 697cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 1.44 (d, 3H, 6.8 Hz, CH₃), 4.22 (s, 2H, CH₂),6.44-6.54 (m, 2H, C³—/C⁵—H 2-amino-Pyr), 7.04-7.35 (m, 9H, Ph and4-F-Ph), 7.80 (d, 1H, 5.4 Hz, C⁶—H 2-amino-Pyr)

{4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]pyridin-2-yl}-(4-methoxybenzyl)amine(26e)

Using the general method C, the title compound was obtained from 26a(0.2 g; 0.5 mmol) and 4-methoxybenzylamine (2.0 g; 14.6 mmol) after areaction time of 22 hours under reflux and separation by columnchromatography (Al₂O₃, CH₂Cl₂/ethyl acetate 1+1). M.p. 196-200° C.

IR (ATR): 1605, 1574, 1507, 1245, 1225 (C—F), 843, 814, 698

¹H-NMR (DMSO-d₆): δ (ppm) 4.29 (s, 2H isomers “A”+“B”, NCH₂), 4.35 (s,2H “A”+“B”, SCH2), 6.43-6.47 (m, 1H “A”+2H “B”, C⁵—H “A” and C³—/C⁵—H“B” 2-amino-Pyr), 6.65 (s, 1H “A”, C³—H2-amino-Pyr), 6.80-6.84 (m, 2H“A”+“B”, 4-MeO-Ph), 7.14-7.51 (m, 11H “A”+“B”, 4-MeO-Ph, Ph and 4-F-Ph),7.79 (d, 1H “B”, 5.4 Hz, C⁶—H 2-amino-Pyr), 7.91 (d, 1H “A”, 5.4 Hz,C⁶—H 2-amino-Pyr), 12.67 (bs, 1H, exchangeable, Imidazole-NH), amino-NHnot visible

4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-2-methoxypyridine(26f)

A suspension of 25a (0.1 g; 0.25 mmol) in methanolic NaOCH₃ solution(30%, 2 ml) was diluted with methanol (5 ml) and stirred under refluxfor 13 h. The reaction mixture was diluted with H₂O and the aqueoussolution was extracted with CH₂Cl₂ (3×). The combined organic extractwas washed with saturated NaCl solution, dried over Na₂SO₄ andconcentrated. The oily residue was purified by column chromatography(SiO₂ 60, CH₂Cl₂/ethyl acetate 1+1).

¹H-NMR (CDCl₃): δ (ppm) 3.91 (s, 3H, OCH₃), 4.29 (s, 2H, CH₂), 6.91-6.95(m, 1H, 2-MeO-Pyr), 7.02-7.11 (m, 2H, 4-F-Ph), 7.27-7.38 (m, 7H, Ph and4-F-Ph), 8.05 (d, 1H, 5.4 Hz, C⁶—H 2-MeO-Pyr), NH not visible

EXAMPLE 27

2-Chloro-4-[5-(4-fluorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl]pyridine(27a)

NaH (55-65%; 0.1 g; about 2 mmol) was introduced into a solution of 24a(0.31 g; 1.0 mmol) in absolute THF (15 ml). The initial charge wasstirred at room temperature for 5 min, and 4-methylsulfinylbenzylchloride (3, 0.19 g; 1.0 mmol) was added. The reaction mixture wasstirred at room temperature for 2 h. The yellow-brown solution wasdiluted with H₂O and neutralized with 10% strength citric acid. The THFwas removed and the aqueous solution was extracted with ethyl acetate(2×). The combined organic extract was washed with saturated NaClsolution (2×), dried over Na₂SO₄ and concentrated. The solids residuewas purified by column chromatography (SiO₂ 60, CH₂Cl₂/EtOH 9.5+0.5).M.p. 179° C.

IR (ATR): 3049, 1592, 1505, 1374, 1224 (C—F), 1086, 1030 (S═O), 1014,989, 839, 816, 781 cm⁻¹ (C—Cl)

¹H-NMR (DMSO-d₆): δ (ppm) 2.71 (s, 3H, CH₃), 4.48 (s, 2H, CH₂),7.25-8.24 (m, 10H, 2-Cl-Pyr, 4-MeS(O)-Ph and 4-F-Ph), 8.26 (d, 1H, 5.3Hz, C⁶—H 2-Cl-Pyr), 12.94 (bs, 1H, exchangeable, NH)

2-Fluoro-4-[5-(4-fluorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl]pyridine(27b)

Using the general method A, the title compound was obtained from 24b(4.2 g; 14.5 mmol) and 3 (4.1 g; 22 mmol) after a reaction time of 2hours and separation by column chromatography (1. Al₂O₃, CH₂Cl₂/ethylacetate 1+1, 2. SiO₂ 60, CH₂Cl₂/EtOH 9+1). M.p. 150° C.

IR (ATR): 3061, 1610, 1506, 1408, 1227 (C—F), 1030 (S═O), 1016, 995,978, 882, 839, 815 cm⁻¹

¹H-NMR (DMSO-d₆): δ (ppm) 2.71 (s, 3H, CH₃), 4.49 (s, 2H, CH₂), 7.10 (s,1H, C³—H2-F-Pyr), 7.30-7.37 (m, 3H, C⁵—H 2-F-Pyr and 4-F-Ph), 7.47-7.67(m, 6H, 4-F-Ph and 4-MeS(O)-Ph), 8.11 (d, 1H, 4,8 Hz, C⁶—H 2-F-Pyr),12.95 (bs, 1H, exchangeable, NH)

Benzyl-{4-[5-(4-fluorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl]pyridin-2-yl}amine(27c)

Using the general method C, the title compound was obtained from 27b(0.3 g; 0.68 mmol) and benzylamine (0.75 g; 7.0 mmol) after a reactiontime of 7 hours at 170° C. and separation by column chromatography (SiO₂60, CH₂Cl₂/ethanol 19+1).

M.p. 149° C.

IR (ATR): 3238, 3064, 1600, 1558, 1514, 1495, 1227 (C—F), 1034 (S═O),1006, 982, 839, 814 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 2.70 (s, 3H, CH₃), 4.21 (s, 2H, NCH₂), 4.32 (s,2H, SCH₂) 6.51-6.55 (m, 2H, C³—/C⁵—H 2-amino-Pyr), 7.03-7.42 (m, 13H.Ph, 4-MeS(O)-Ph and 4-F-Ph), 7.82 (d, 1H, 5.5 Hz, C⁶—H 2-amino-Pyr)

(RS)-{4-[5-(4-Fluorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl]pyridin-2-yl}-(1-phenylethyl)amine(27d)

Using the general method C, the title compound was obtained from 27b(0.3 g; 0.68 mmol) and (RS)-1-phenylethylamine (0.85 g; 7.0 mmol) aftera reaction time of 10 hours at 170° C. and separation by columnchromatography (SiO₂ 60, CH₂Cl₂/ethanol 9+1). M.p. 193° C.

IR (ATR): 2967, 1606, 1547, 1502, 1221 (C—F), 1085, 1031 (S═O), 1014,838, 814, 670 cm⁻¹

¹H-NMR (CD₃OD): δ (ppm) 1.45 (d, 3H, 6.8 Hz, CH₃), 2.67 (s, 3H,S(O)CH₃), 4.28 (s, 2H, CH₂), 4.62-4.73 (m, 1H, methyne-H), 6.42-6.53 (m,2H, C³—/C⁵—H 2-amino 7.09-7.44 (m, 9H, Ph and 4-F-Ph), ), 8.21 (d, 1 H,5.0 Hz, C⁶—H 2-F-Pyr).

Compounds obtained by method C are compiled in Table 3 below (however,compound no. 31 was obtained by method D):

TABLE 3 1H-NMR

Example ¹H-NMR spectrum No. R³ Solvent δ(ppm) 28

DMSO-d6 2.59 (s, 3H, —SCH3), 4.59 (t, 2H, J=4.74 Hz, >N—CH2—), 6.46-6.71(m, 2H, C3-/C5-H 2- amino-Pyr), 6.91-6.94 (m, 2H, thiophene), 7.07 (t,1H, exchangeable, J=4.7 Hz, Pyr-NH—), 7.16-7.23 (m, 1H, thiophene),7.28-7.35 (m, 2H, 4-F-Phe), 7.41-7.50 (m, 2H, 4-F-Phe), 7.82- 7.96 (m,1H, C6-H 2-amino-Pyr), 12.61 (s, 1H, exchangeable, imidazole-NH) 29

DMSO-d6 2.60 (s, 3H, —SCH3), 4.41 (d, 2H, J=5.74 Hz, >N—CH2—), 6.17 (d,1H, J=3.12 Hz, C3-H furan), 6.34-6.37 (m, 1H, C4-H furan), 6.46-6.49 (m,1H, C5-H 2-amino-Pyr), 6.65 (s, 1H, C3-H 2-amino-Pyr), 6.95 (t, 1H,J=6.00 Hz, Pyr-NH—), 7.18-7.27 (m, 2H, 4-F-Phe), 7.44-7.55 (m, 3H, C5-Hfuran and 4-F-Phe), 7.88 (d, 1H, J=4.70 Hz, C6-H 2-amino-Pyr), 12.62 (s,1H, imidazole-NH) 30

DMSO-d6 1.47-1.53 (m, 1H, C3-H tetrahydrofuran), 1.75-1.88 (m, 3H,C3-/C5-H tetrahydrofuran), 2.59 (s, 3H, —SCH3), 3.20-3.28 (m,2H, >N—CH2—), 3.55-3.61 (m, 1H, C5-H tetrahydrofuran), 3.69-3.76 (m, 1H,C5-H tetrahydrofuran), 3.89-3.93 (m, 1H, methyne-Htetrahydrofurfurylamine), 6.39–6.68 (m, 3H, C3-/C5-H 2-amino-Pyr andPyr-NH— (1H exchangeable)), 7.15–7.31 (m, 2H, 4-F-Phe), 7.41–7.50 (m,2H, 4-F-Phe), 7.76–7.92 (m, 1H, C6-H 2-amino-Pyr), 12.58 (s, 1H,exchangeable, imidazole-NH) 31

CD3OD 2.6 (s, 3H, —SCH3), 4.54 (s, 2H, >N—CH2—), 6.60 (d, 2H, J=4.16 Hz,C3-/C5-H 2 amino-Pyr), 7.03–7.12 (m, 2H, 4-F-Phe), 7.27–7.44 (m, 4H,C3-/C5-H 2-(aminomethyl)pyridine and 4-F-Phe), 7.71–7.80 (m, 1H, C4-H2-(aminomethyl)pyridine), 7.84 (d, 1H, J=6.04 Hz, C6-H 2-amino-Pyr),8.43–8.46 (m, 1H, C6-H 2-(aminomethyl)pyridine) 32

CD3OD 2.60 (s, 3H, —SCH3), 4.48 (s, 2H, >N—CH2—), 6.59–6.62 (m, 2H,C3-/C5-H 2-amino-Pyr), 7.06–7.14 (m, 2H, 4-F-Phe), 7.34–7.45 (m, 3H,4-F-Phe and C5-H 3-(aminomethyl)pyridine), 7.73–7.78 (m, 1H, C4-H3-(aminomethyl)pyridine), 7.84 (d, 1H, J=6.18 Hz, C6-H 2-amino-Pyr),8.37–8.40 (m, 1H, C6-H 3-(aminomethyl)pyridine), 8.44–8.45 (m, 1H, C2-H3-(aminomethyl)pyridine) 33

DMSO-d6         CD3OD 0.78–0.92 (m, 2H, cyclohexane), 1.10–1.22 (m, 3H,cyclohexane), 1.42–1.45 (m, 1H, methyne-H, cyclohexylmethylamine),1.64–1.70 (d, 5H, J=10.49 Hz, cyclohexane), 2.59 (s, 3H, —SCH3),2.93–3.02 (m, 2H, >N—CH2—), 6.39–6.60 (m, 3H, C3-/C5-H 2-amino-Pyr andPyr-NH—, (1H exchangeable)), 7.12–7.31 (m, 2H, 4-F-Phe), 7.40–7.53 (m,2H, 4-F-Phe), 7.76–7.91 (m, 1H, C6-H 2-amino-Pyr), 12.60 (s, 1H,exchangeable, imidazole-NH) 0.93 (t, 2H, J=11.05 Hz, cyclohexane),1.17–1.28 (m, 3H, cyclohexane), 1.40–1.49 (m, 1H, methyne-H,cyclohexane), 1.75 (d, 5H, J=11.47 Hz, cyclohexane), 2.62 (s, 3H,—SCH3), 2.96–2.99 (m, 2H, >NH—CH2—), 6.54 (d, 2H, J=5.10 Hz, C3-/C5-H2-amino-Pyr), 7.14 (t, 2H, J=8.77 Hz, 4-F-Phe), 7.43–7.50 (m, 2H,4-F-Phe), 7.80 (d, 1H, J=5.52 Hz, C6-H 2-amino-Pyr) 34

CD3OD 1.75-1.86 (m, 1H, C3-H 1-aminoindane), 2.45-2.53 (m, 1H, C3-H1-aminoindane), 2.61 (s, 3H, —SCH3), 2.82–32.96 (m, 2H, C2-H,1-aminoindane), 5.25 (t, 1H, J=7.29 Hz, methyne-H 1- aminoindane),6.56–6.59 (m, 1H, C5-H 2-amino-Pyr), 6.67 (s, 1H, C3-H 2-amino-Pyr),7.07–7.25 (m, 6H, C4-/C5-/C6-/C7-H 1-aminoindane and 4-F-Phe), 7.42–7.49(m, 2H, 4-F-Phe), 7.84–7.87 (m, 1H, C6-H 2-amino-Pyr) 35

CD3OD 2.62 (s, 3H, —SCH3), 3.04 (t, 2H, J=7.02 Hz, —CH2—2-(2-thienyl)ethylamine)), 3.47 (t, 2H, J=7.04 Hz, >N—CH2—2-(2-thienyl)ethylamine)), 6.56–6.59 (m, 2H, C3-/C5-H 2-amino-Pyr),6.83–6.85 (m, 1H, C3-H thiophene), 6.89–6.94 (m, 1H, C4-H thiophene),7.09–7.20 (m, 3H, 4-F-Phe and C5-H thiophene), 7.43–7.50 (m, 2H,4-F-Phe), 7.84 (d, 1H, J=6.12 Hz, C6-H 2-amino-Pyr) 36

CD3OD 2.58 (s, 3H, —SCH3), 3.00–3.03 (m, 2H, —CH2—1,2-diphenylethylamine), 4.73 (t, 1H, J=7.20 Hz, methyne-H1,2-diphenylethylamine), 6.40 (s, 1H, C3-H 2-amino-Pyr), 6.55 (d, 1H,J=5.44 Hz, C5-H 2-amino-Pyr), 7.05-7.40 (m, 14H, 4-F-Phe and Ar-H 1,2diphenylethylamine), 7.77 (d, 1H, J=5.44 Hz, C6-H 2-amino-Pyr)

EXAMPLE 37a

Cyclohexyl-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine(37a)

2-Fluoro-4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine (1.2 g, 4 mmol), which had been weighed outinto a 25 ml one-necked flask which had been flushed with argonbeforehand, was suspended in cyclohexylamine (3.97 g, 0.04 mol), coveredwith argon and then heated with reflux of the amine, in an oil bath at atemperature of 160° C., for 48 h. The brown suspension is allowed tocool to RT. 30 ml of Na citrate solution (10% strength citric acidsolution pH 5 with conc. NaOH) are then added, and the mixture isstirred for 10 min. and extracted twice with 30 ml of ethyl acetate.

The combined organic phases are extracted twice again with in each case30 ml of Na citrate solution (10% strength citric acid solution pH 5with conc. NaOH) and then with 30 ml of NaHCO₃ solution and extractedonce with saturated NaCl solution. The organic phase is dried overNa₂SO₄ and concentrated using a rotary evaporator, and the residue iscrystallized from 10 ml.

Recrystallization is carried out from isopropanol/water (about 5 ml ofISOH are heated and allowed to cool, and about 5 ml of dist. water areadded slowly). Yield: 0.76 g (49.7%) of a purity (HPLC) of 96.6%.

The compounds of the formula I compiled in Table 4 below are obtainedusing this method:

TABLE 4 Ex. Method Name Structure 37b C 4-[5-(4-Fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]- 2-methoxypyridine

37c C Cyclohexyl-{4-[5-(4-fluorophenyl)-2-isopropylsulfanyl-1H-imidazol-4- yl]pyridine-2-yl}amine

37d C Cyclohexyl-{4-[5-(4-fluorophenyl)-2-(2,2,2-trifluoro-ethylsulfanyl)-1H- imidazol-4-yl]pyridin-2-yl}amine

37e C Cyclohexyl-{4-[5-(2,4- difluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-amine

37f C Cyclohexyl-{4-[5-(2,4- difluorophenyl)-2-ethylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

37g C Cyclohexyl-{4-[5-(2,4- difluorophenyl)-2-isopropylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

37h C Cyclohexyl-{4-[5-(2,4- difluorophenyl)-2-(2,2,2-trifluoro-ethylsulfonyl)-1H-imidazol-4- yl]pyridin-2-yl}amine

37i C Cyclohexyl-{4-[2-methylsulfanyl-5- (3-trifluoromethylphenyl)-1H-imidazol-4-yl]pyridin-2-yl}amine

37j C Cyclohexyl-{4-[2-ethylsulfanyl-5- (3-trifluoromethylphenyl)-1H-imidazol-4-yl]pyridin-2-yl}amine

The compounds compiled in Table 5 below were obtained using the abovemethod:

TABLE 5 Ex. Process Name Structure 38 G 4-[5-(4-Fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]- pyridin-2-ylamine

39 C Methyl-{4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

40 C Ethyl-{4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

41 C Isopropyl-{4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

42 C Methoxyethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

43 C N,N-Dimethylaminoethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

44 C Hydroxypropyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

45 C N′-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-N,N- diphenylethane-1,2-diamine

46 H Cinnamyl-{4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

47 C Cyclopropyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

48 C Cyclopropylmethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

49 C Cycloheptyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

50 C Bicyclo[2.2.1]hept-2-yl-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine

51 C Adamantan-1-yl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

52 C Adamantan-2-yl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

53 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-pyridin-2-yl}-(tetrahydrofuran-3- yl)-amine

54 H {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-pyridin-2-yl}-(tetrahydropyran-4- yl)amine

55 C (1-Ethylpyrrolidin-2-ylmethyl)-{4- [5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}amine

56 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(2-piperidin-1- ylethyl)amine

57 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(2-morpholin-4- ylethyl)amine

58 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(1-methylpiperidin- 4-yl)-amine

59 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-[2-(4- methylpiperazin-1-yl)ethyl]amine

60 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(1-naphthalen-2- ylethyl)amine

61 H 2,2-Diphenylethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

62 H Biphenyl-2-ylmethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

63 H {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(3- phenylpropyl)amine

64 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-indan-2-ylamine

65 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(1,2,3,4- tetrahydronaphthalen-1-yl)amine

66 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(1,2,3,4- tetrahydronaphthalen-2-yl)amine

67 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}quinolin-2- ylmethylamine

68 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl]pyridin-4- ylmethylamine

69 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-quinolin-4- ylmethylamine

70 H [1-(5-Chlorothiophen-2-yl)ethyl]- {4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}amine

71 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-thiophen-3- ylmethylamine

72 C Benzo[b]thiophen-2-ylmethyl-{4- [5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}amine

73 C Benzofuran-2-ylmethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

74 H (1-Benzofuran-2-yl-ethyl)-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine

75 C (2,3-Dihydrobenzofuran-2- ylmethyl)-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4- yl]pyridine-2-yl}amine

76 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-oxazol-2- ylmethylamine

77 C Benzoxazol-2-ylmethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}amine

78 C 2-({4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-ylamino}methyl)-4- isopropyloxazol-5-ol

79 C N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-N′-(2- methylsulfanylvinyl)formamidine

80 C N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-N′-(1-methyl-2- methylsulfanylpropenyl)formamidine

81 C N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-N′-(2-methyl- sulfanylphenyl)formamidine

82 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(2-methylthiazol-5- ylmethyl)amine

83 C {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(2-methylthiazol-4- ylmethyl)amine

84 C {4-[5-(4-Fluorophenyl)-2-methyl- sulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-[2-(2-methyleneamino- phenylsulfanyl)-ethyl]amine

85 B 2-Bromo-4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridine

86 G 2-Azido-4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridine

87 D 2-Ethoxy-4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridine

88 C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-p-tolyloxypyridine

89 C 2-(2.6-Dichlorophenoxy)-4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine

90 D 2-Benzyloxy-4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine

91 D 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-phenethyloxypyridine

92 D 2-Cyclohexyloxy-4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine

93 C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-(tetrahydrofuran-3-yloxy)pyridine

94 D 6-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yloxy}hexa- hydrofuro[3.2-b]furan-3-ol

95 C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-(tetrahydrofuran-2- ylmethoxy)pyridine

96 C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-(tetrahydropyran-2-ylmethoxy)- pyridine

97 C 2-(Benzofuran-2-ylmethoxy)-4-[5- (4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine

98 C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-(furan-2-ylmethoxy)pyridine

99 C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-(thiophen-2-ylmethoxy)pyridine

100  C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-(5-chlorothiophen-2-yl- methoxy)pyridine

101  C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-(thiophen-3-ylmethoxy)pyridine

102  C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-(thiazol-2-ylmethoxy)pyridine

103  C Bicyclo[2.2.1]hept-2-yl-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine

104  C 3-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yloxy}-1- azabicyclo[2.2.2]octane

105  C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-methylsulfanylpyridine

106  C 2-Benzenesulfonyl-4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine

107  C 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-2-phenylsulfanylpyridine

108  C 2-Ethylsulfanyl-4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine

109  C 2-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-ylsulfanyl}ethanol

110  C 3-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-ylsulfanyl]propan-1-ol

110a E N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}formamide

111  E N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}benzamide

112  E 4-Chloro-N-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}benzamide

113  E N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-3- methylbenzamide

114  E N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-3- trifluoromethylbenzamide

115  F N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-2-phenylacetamide

116  F Cyclohexanecarboxylic acid {4-[5-(4-fluorophenyl)-2-methylsulfanyl- 1H-imidazol-4-yl]pyridin-2- yl}amide

117  F 2-Cyclohexyl-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2- yl}acetamide

118  F 2-(4-Chlorophenyl)-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2- yl}acetamide

119  F N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-2-(4- methoxyphenyl)acetamide

120  F 2-(4-Fluorophenyl)-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}acetamide

121  F 2-(2-Fluorophenyl)-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2- yl}acetamide

122  F N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-pyridin-2-yl}-3-phenylpropionamide

123  F N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-3-phenylacrylamide

124  F {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-carbamic acid benzyl ester

125  F 1-Benzoyl-3-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}urea

126  E N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl]acetamide

127  F 2.2,2-Trifluoro-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2- yl}acetamide

128  F N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-2- methoxyacetamide

129  F N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-2- (methylphenylamino)acetamide

130  F {4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-carbamic acid cyclohexyl ester

131  C {4-[5-(2,4-Difluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}isopropylamine

132  C {4-[5-(2,4-Difluorophenyl)-2- ethylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}isopropylamine

133  C {4-[5-(2,4-Difluorophenyl)-2- isopropylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}isopropylamine

134  F Isopropyl-{4-[2-methylsulfanyl-5- (3-trifluoromethylphenyl)-1H-imidazol-4-yl]pyridin-2-yl}amine

135  F {4-[2-Ethylsulfanyl-5-(3- trifluoromethylphenyl)-1H-imidazol-4-yl]pyridin-2- yl}isopropylamine

136  F {4-[5-(2,4-Difluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl}-(2- methoxyethyl)amine

137  F {4-[5-(4-Fluorophenyl)-2- methylsulfonyl-1H-imidazol-4-yl]pyridin-2-yl}urea

138  F N-{4-[5-(4-Fluorophenyl)-2- methylsulfonyl-1H-imidazol-4-yl]pyridin-2-yl-2-(4- isobutylphenyl)propionamide

1. A 2-thio-substituted imidazole derivative compound of the formula I

wherein R¹ is aryl which may or may not be substituted by a halogenatom; R² is selected from the group consisting of a) aryl-C₁-C₄-alkyl,and b) C₁-C₆-alkyl; R³ is selected from the group consisting of a)NR⁴R¹⁰ b) NR⁷COR¹⁰, and c) C₁-C₆-alkoxy; R⁴ is H; R¹⁰ is

or, if R³ is NR⁷COR¹⁰, R¹⁰ is R⁸, R⁵ and R⁶, which may be identical ordifferent, are H, halogen, C₁-C₆-alkoxy or C₁-C₆-alkyl; R⁷ is H,C₁-C₆-alkyl or benzyl; R⁸ is C₁-C₄-alkyl, C₃-C₆-cycloalkyl or phenyl,where the phenyl group may have one or two substituents independently ofone another selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-alkoxy and halogen; A is straight-chain or branched C₁-C₆-alkyleneor C₂-C₆-alkenylene and m is 0, 1 or 2; or a tautomer, an optical isomeror a physiologically acceptable salt thereof.
 2. The compound as claimedin claim 1, which has the formula Ia:


3. The compound as claimed in claim 1, wherein R³ is


4. The compound as claimed in claim 3, wherein A is C₁-C₂-alkylene. 5.The compound as claimed in claim 3, wherein A is ethylidene.
 6. Thecompound as claimed in claim 3, wherein R⁵ and R⁶ are H.
 7. The compoundas claimed in claim 1, wherein R¹ is 4-fluorophenyl.
 8. A pharmaceuticalcomposition, comprising at least one compound as claimed in claim 1, andone or more pharmaceutically acceptable carriers and/or additives.
 9. Amethod for treating inflammatory disorders in which TNF-α and IL-β areinvolved which comprises administering to a person in need of such atreatment an amount of a compound as claimed in claim 1 sufficient tohave anti-inflammatory action.
 10. A 2-thio-substituted imidazolederivative compound of the formula I

wherein R¹ is aryl which is substituted by a halogen atom or byhalo-C₁-C₆-alkyl; R² is selected from the group consisting of a)aryl-C₁-C₄-alkyl, and b) C₁-C₆-alkyl; R³ selected from the groupconsisting of a) NR⁴R¹⁰, b) NR⁷COR¹⁰, c) OR¹⁰, and d) NH₂; R⁴ is H,—COR¹⁴, —CO₂R¹⁴, —CONH₂, —CONHR¹⁴, —CHR¹⁶—OR¹⁴, —CHR¹⁶—O—COR¹⁴,—COC(R¹⁶)₂—OH, —COR¹⁵, SO₂R¹⁵ or —SO₂R¹⁴, R¹⁴ is C₁-C₆-alkyl or CF₃, R¹⁵is phenyl or tolyl, and R¹⁶ is H or C₁-C₆-alkyl; R⁵ and R⁶, which may beidentical or different, are H, halogen, C₁-C₆-alkoxy, C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R⁷ is H; R¹⁰ has one of the meanings below:

f) C₁-C₆-alkyl which is substituted by 2 phenyl groups, or g)trifluoromethyl; A is straight-chain or branched C₁-C₆-alkylene orC₂-C₆-alkenylene; B is selected from the group consisting of

e) OC₁-C₆-alkyl, and f) OH; Hy is a 3- to 10-membered non-aromaticmono-, bi- or tricyclic carbocycle which may or may not be fused with abenzene ring; Ar is a 5- or 6-membered aromatic heterocycle which has 1,2 or 3 heteroatoms independently of one another selected from the groupconsisting of O, S and N and which may or may not be fused with abenzene ring; Het is a 5- or 6-membered non-aromatic heterocycle whichhas 1, 2 or 3 heteroatoms independently of one another selected from thegroup consisting of O, S and N which may or may not be fused with abenzene ring and which may or may not be bridged bicyclically ortricyclically; m is 0, 1 or 2; or a tautomer, an optical isomer or aphysiologically acceptable salt thereof.
 11. The compound as claimed inclaim 10, which has formula Ia:


12. The compound as claimed in claim 10, wherein R¹⁰ is A-B and B isselected from the group consisting of OC₁-C₆-alkyl and OH.
 13. Thecompound as claimed in claim 10, wherein R³ is NR⁷COR¹⁰, and R¹⁰ isselected from the group consisting of —O—C₁-C₄-alkylphenyl, phenyl andC₂-C₆-alkenyl which is substituted by phenyl.
 14. The compound asclaimed in claim 10, wherein A is C₁-C₂-alkylene.
 15. The compound asclaimed in claim 10, wherein A is ethylidene.
 16. The compound asclaimed in claim 10, wherein R⁵ and R⁶ are H.
 17. The compound asclaimed in claim 10, wherein R¹ is halogen-substituted phenyl orCF₃-substituted phenyl.
 18. A pharmaceutical composition, comprising atleast one compound as claimed in claim 10, and one or morepharmaceutically acceptable carriers and/or additives.
 19. A method fortreating inflammatory disorders in which TNF-α and IL-β are involvedwhich comprises administering to a person in need of such a treatment anamount of a compound as claimed in claim 10 sufficient to haveanti-inflammatory action.
 20. The compound as claimed in claim 10, whichis{4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]-pyridin-2-yl}-(tetrahydropyran-4-yl)amine.
 21. The method according to claim 9,wherein the inflammatory disorder is rheumatoid arthritis.
 22. Themethod according to claim 19, wherein the inflammatory disorder isrheumatoid arthritis.
 23. The compound as claimed in claim 10, whereinR¹⁰ has one of the meanings below:

f) C₁-C₆-alkyl which is substituted by 2 phenyl groups, or g)trifluoromethyl; and when R¹⁰ is A-B, B is selected from the groupconsisting of a) H,

e) OC₁-C₆-alkyl, and f) OH.